****2018 SRC Herein, we report a rare case of SRC carcinoma associated with poorly differentiated adenocarcinoma of the non-ampullary duodenum in a 74-year-old woman. Based on the morphological features and the immunohistochemical profile, a diagnosis of SRC carcinoma associated with poorly differentiated adenocarcinoma of the non-ampullary duodenum was set. Here, we evaluate the potential involvement of SRC family kinases (SFK) in lung cancer biology and assess the possible benefits of their inhibition as a therapeutic approach. We demonstrated that various SRC family members, including LYN and LCK, normally expressed solely in hematopoietic cells and neural tissues, are overexpressed and activated in a panel of SCLC and NSCLC cell lines. Splice-form-specific depletion and rescue experiments further identify the ΔNp63γ isoform as both necessary and sufficient to activate the SRC signaling axis and SNAI2-mediated EMT and invasion. Moreover, elevated SRC levels are associated with poor outcome in patients with HNSCC in The Cancer Genome Atlas dataset. Importantly, the effects on EMT and invasions and SNAI2 expression can be reversed by genetic or pharmacologic inhibition of SRC.Conclusions: Overexpression of ΔNp63γ modulates cell invasion by inducing targetable SRC-Slug-evoked EMT in HNSCC, which can be reversed by inhibitors of the SRC signaling. Integrated use of bioinformatic resources reveals that co-targeting of histone deacetylases, IKBK and SRC inhibits epithelial-mesenchymal transition in cancer. Barneh F(1)(2), Mirzaie M(3), Nickchi P(2)(4), Tan TZ(5), Thiery JP(6)(7)(8), Piran M(2), Salimi M(9), Goshadrou F(1), Aref AR(10), Jafari M(2). Author information: (1)Department of Basic Sciences, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (2)Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran. (3)Department of Applied Mathematics, Faculty of Mathematical Sciences, Tarbiat Modares University, Tehran, Iran. (4)Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, BC, Canada. (5)Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore, Translational Centre for Development and Research, National University Health System, MD11, #03-10, 10 Medical Drive, Singapore 117597, Singapore. (6)Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore. (7)Institut Gustave Roussy, Inserm Unit 1186 Comprehensive Cancer Center, Villejuif, France. (8)CNRS UMR 7057 Matter and Complex Systems, University Paris Denis Diderot, Paris, France. (9)Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran. (10)Department of Medical Oncology, Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston 02215, USA. With the advent of high-throughput technologies leading to big data generation, increasing number of gene signatures are being published to predict various features of diseases such as prognosis and patient survival. Moreover, SRC and IKBK were the principal intracellular kinases regulating multiple signaling pathways. Molecular analyses revealed that high expression of the signal transducer and activator of transcription 3 (STAT3)- Kirsten rat sarcoma viral oncogene homolog (KRAS) and proto-oncogene tyrosine-protein kinase SRC axis supports MerTK-induced CSC maintenance in GBM spheroids. Oncotarget. 2017 Dec 20;9(4):4722-4736. doi: 10.18632/oncotarget.23524. eCollection 2018 Jan 12. Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer. McGivern N(1), El-Helali A(1), Mullan P(1), McNeish IA(2), Paul Harkin D(1)(3), Kennedy RD(1)(3), McCabe N(1)(3). Author information: (1)Centre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland, UK. (2)Institute of Cancer Sciences, University of Glasgow, Scotland, UK. (3)Almac Diagnostics, 19 Seagoe Industrial Estate, Craigavon, Northern Ireland, UK. SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease. In this study we aimed to identify mechanisms of resistance to SRC inhibitors in ovarian cancer cells. Furthermore, we demonstrate a synergistic effect of combining SRC and MEK inhibitors in both AZD0530 sensitive and resistant cells, and that MEK inhibition is sufficient to completely resensitize AZD0530 resistant cells. This work provides a preclinical rationale for the combination of SRC and MEK inhibitors in the treatment of ovarian cancer, and also highlights the need for biomarker driven patient selection for clinical trials. DOI: 10.18632/oncotarget.23524 PMCID: PMC5797008 Dasatinib is a potent inhibitor of BCR-ABL, KIT, and SRC family kinases as well as imatinib-resistant cells. In myxoid and round cell liposarcoma (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one of the most activated kinases. The involvement of SRC/FAK activation in FUS-CHOP-mediated invasion was further confirmed using the SRC inhibitor dasatinib, the specific FAK inhibitor PF-573228, and FAK siRNA. PID 29940643 29937990 29739791 29726962 29553850 29435137 29315500 29190494 LIG1 PID HDAC7 PID MIF eCollection 2018. Macrophage Migration Inhibitory Factor protects cancer cells from immunogenic cell death and impairs anti-tumor immune responses. Balogh KN(1), Templeton DJ(1), Cross JV(1). Author information: (1)Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, United States of America. The Macrophage Migration Inhibitory Factor (MIF) is an inflammatory cytokine that is overexpressed in a number of cancer types, with increased MIF expression often correlating with tumor aggressiveness and poor patient outcomes. In this study, we aimed to better understand the link between primary tumor expression of MIF and increased tumor growth. Using the MMTV-PyMT murine model of breast cancer, we observed that elevated MIF expression promoted tumor appearance and growth. Supporting this, we confirmed our previous observation that higher MIF expression supported tumor growth in the 4T1 murine model of breast cancer. We subsequently discovered that loss of MIF expression in 4T1 cells led to decreased cell numbers and increased apoptosis in vitro under reduced serum culture conditions. Supporting this, we demonstrated that loss of MIF expression in the primary tumor led to an increased abundance of intra-tumoral IFNgamma-producing CD4+ and CD8+ T cells, and that depletion of T cells from mice bearing MIF-deficient tumors restored growth to the level of MIF-expressing tumors. Furthermore, we found that MIF depletion from the tumor cells resulted in greater numbers of activated intra-tumoral dendritic cells (DCs). Lastly, we demonstrated that loss of MIF expression led to a robust induction of a specialized form of cell death, immunogenic cell death (ICD), in vitro. Together, our data suggests a model in which MIF expression in the primary tumor dampens the anti-tumor immune response, promoting tumor growth. DOI: 10.1371/journal.pone.0197702 PMCID: PMC5986154 PID 29864117 TUBB PID NET1 PID PAK2 PID PAK1 PID CLASP1 PID BRCC3 PID RAC3 PID PAK3 PID E2F1 Transcriptional profiling of BRD4-transformed ovarian cells, and BRD4-amplified HGSOC patient samples revealed shared expression patterns, including enriched MYC, and E2F1 gene signatures. We report that the transcriptional inhibitor, E2F7, is mislocalized to the cytoplasm in >80% of human HNSCCs, whereas the transcriptional activator, E2F1, retains localization to the nucleus in SCC. More generally, we provide a strategy to restore the balance of E2F1 (activator) and E2F7 (inhibitor) activity in cancer. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. 18. ANP32E induces tumorigenesis of triple-negative breast cancer cells by upregulating E2F1. Xiong Z(1), Ye L(2), Zhenyu H(3), Li F(3), Xiong Y(4), Lin C(2), Wu X(2), Deng G(1), Shi W(5), Song L(2), Yuan Z(5), Wang X(1). Author information: (1)Department of Breast Surgery, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. (2)Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. (3)Department of Radiation Oncology, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. (4)The First College of Clinical Medicine, Southern Medical University, Guangzhou, China. (5)Department of Medical Oncology, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor, and the HER2 receptor; it is highly proliferative and becomes the deadliest forms of breast cancer. By examining the expression of E2F1, cyclin E1, and cyclin E2, we discovered that ANP32E promotes the G1/S transition by transcriptionally inducing E2F1. Taken together, our study shows that ANP32E is an efficient prognostic marker, and it promotes the G1/S transition and induces tumorigenesis of TNBC cells by transcriptionally inducing E2F1. © 2018 The Authors. Finally, ERLIN1, HMGA2, FAM110B, EGFR, MCM2, BCL2L1, E2F1 and RAC1 were associated with the survival time of pancreatic adenocarcinoma patient. CONCLUSIONS: 12 tumor differentiation related genes including JUB, ERLIN1, HMGA2, FAM110B, EGFR, MCM2, TCTA, SSTR1, BCL2L1, E2F1, RAC1 and STAT1 played crucial roles in the differentiation of pancreatic adenocarcinoma. DOI: 10.1371/journal.pone.0193427 PMCID: PMC5875763 Cancer-testis Specific Gene OIP5: A Downstream Gene of E2F1 that Promotes Tumorigenesis and Metastasis in Glioblastoma by Stabilizing E2F1 Signalling. He J(1), Zhao Y(1), Zhao E(1), Wang X(1), Dong Z(1), Chen Y(1), Yang L(1), Cui H(1). Author information: (1)State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China. Background: The cancer-testis specific gene Opa interacting protein 5 (OIP5) is a testis-specific gene that is reactivated in many human cancers, but its functions in glioblastoma remain unclear. Tumorigenicity potential was investigated in orthotopic tumour models, and immunoprecipitation, chromatin immunoprecipitation, and luciferase assays were employed to explore the mechanisms underlying the activation of OIP5 expression by E2F transcription factor 1 (E2F1) to stabilize and maintain E2F1 signalling. Notably, we demonstrated a feed-back loop in which E2F1 activates the expression of OIP5 to stabilize and maintain E2F1 signalling, promote the E2F1-regulated gene expression that is required for aggressive tumour biology. EPEL interacted with E2F1 and regulated the expression of the E2F target genes by changing the binding efficiency of E2F1 to the E2F target promoters. ANXA3 small interfering RNA (siRNA) also reduced the expression of cycle-dependent kinase protein and increased the expression of E2F1 and p27 proteins compared with control siRNA. PID 30036377 29950445 29633513 29596435 29547938 29448242 29217453 GNAO1 PID TUBB2A PID CDK2 Intriguingly, the signalling molecules perturbed by CCRK are divergent and cancer-specific, including the cell cycle regulators CDK2, cyclin D1, cyclin E and RB in glioblastoma, ovarian carcinoma and colorectal cancer, and KEAP1-NRF2 cytoprotective pathway in lung cancer. PID 29360538 USP21 PID KIF2A PID HDAC9 PID KLC2 PID DYNLL1 PID TUBB1 PID ATF2 PID METAP2 PID LRIG1 9. LRIG1 negatively regulates RET mutants and is downregulated in thyroid cancer. Lindquist D(1), Alsina FC(2), Herdenberg C(1), Larsson C(3), Höppener J(4), Wang N(3), Paratcha G(2), Tarján M(5), Tot T(5), Henriksson R(1), Hedman H(1). Author information: (1)Oncology Research Laboratory, Department of Radiation Sciences, Umeå University, SE-90187 Umeå, Sweden. (2)Institute of Cell Biology and Neuroscience (IBCN)-CONICET, School of Medicine, University of Buenos Aires (UBA), Buenos Aires 1121, Argentina. (3)Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska University Hospital, 171 76 Stockholm, Sweden. (4)University Medical Center Utrecht, Division of Biomedical Genetics and Laboratory of Translational Immunology, 3508 GA Utrecht, The Netherlands. (5)Department of Pathology and Clinical Cytology, Central Hospital Falun, 791 82 Falun, Sweden. Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) are characterized by genomic rearrangements and point mutations in the proto-oncogene RET. LRIG1 expression levels are associated with patient survival in many cancer types. In the present study, we investigated whether the oncogenic RET mutants RET2A (C634R) and RET2B (M918T) were regulated by LRIG1, and the possible effects of LRIG1 expression in thyroid cancer were investigated in three different clinical cohorts and in a RET2B-driven mouse model of MTC. LRIG1 was shown to physically interact with both RET2A and RET2B and to restrict their ligand-independent activation. LRIG1 mRNA levels were downregulated in PTC and MTC compared to normal thyroid gland tissue. There was no apparent association between LRIG1 RNA or protein expression levels and patient survival in the studied cohorts. There was no significant difference in the incidence of pre-cancerous lesions between Lrig1 wild-type and Lrig1-deficient RET2B mice. In conclusion, the findings that LRIG1 is a negative regulator of RET2A and RET2B and is also downregulated in PTC and MTC may suggest that LRIG1 functions as a thyroid tumor suppressor. DOI: 10.3892/ijo.2018.4273 PMCID: PMC5843404 PID 29436694 PARD3 PID PKN1 PID PKN2 PID PRICKLE1 PID PTPRU PID STK4 PID PAN2 PID ADCY3 PID HIST3H3 PID HK2 Silencing the expression of CXCL1 decreased the levels of the glycolytic enzymes GLUT1, HK2, and LDHA. Our results revealed the loss of miR-155 hampers glucose uptake and glycolysis, via the down-regulation of glucose transporters and metabolic enzymes including HK2, PKM2, and LDHA. PID 29784873 29527004 PPP2R5E PID PPP2R5A PID PRKCA PID ADAM17 J Cancer. 2018 Jun 23;9(14):2559-2570. doi: 10.7150/jca.24601. eCollection 2018. ADAM10 Sheddase Activity is a Potential Lung-Cancer Biomarker. Yoneyama T(1)(2), Gorry M(1)(2), Sobo-Vujanovic A(1)(2), Lin Y(3), Vujanovic L(4), Gaither-Davis A(4), Moss ML(5), Miller MA(6), Griffith LG(7), Lauffenburger DA(6)(7), Stabile LP(8), Herman J(4), Vujanovic NL(1)(9)(2). Author information: (1)Department of Pathology, University of Pittsburgh; UPMC Hillman Cancer Center, Pittsburgh, PA. (2)VAPHS, Pittsburgh, PA. (3)Department of Biostatistics, University of Pittsburgh; UPMC Hillman Cancer Center, Pittsburgh, PA. (4)Department of Medicine, University of Pittsburgh; UPMC Hillman Cancer Center, Pittsburgh, PA. (5)BioZyme Inc, Apex, NC. (6)Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA. (7)Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA. (8)Department of Pharmacology and Chemical Biology, University of Pittsburgh; UPMC Hillman Cancer Center, Pittsburgh, PA. (9)Department of Immunology, University of Pittsburgh; UPMC Hillman Cancer Center, Pittsburgh, PA. Background: Increases in expression of ADAM10 and ADAM17 genes and proteins are inconsistently found in cancer lesions, and are not validated as clinically useful biomarkers. Methods: Using a recent modification of the proteolytic activity matrix analysis (PrAMA) measuring specific enzyme activities in cell and tissue lysates, we examined the specific sheddase activities of ADAM10 (ADAM10sa) and ADAM17 (ADAM17sa) in human non-small cell lung-carcinoma (NSCLC) cell lines, patient primary tumors and blood exosomes, and the noncancerous counterparts. Oncotarget. 2018 Mar 23;9(22):16043-16058. doi: 10.18632/oncotarget.24682. eCollection 2018 Mar 23. ADAM17 inhibition enhances platinum efficiency in ovarian cancer. Hedemann N(1), Rogmans C(1), Sebens S(2), Wesch D(3), Reichert M(4), Schmidt-Arras D(4), Oberg HH(3), Pecks U(1), van Mackelenbergh M(1), Weimer J(1), Arnold N(1), Maass N(1), Bauerschlag DO(1). Author information: (1)Department of Gynecology and Obstetrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany. (2)Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany. (3)Institute of Immunology, Christian-Albrechts-University and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany. (4)Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany. Chemotherapeutic resistance evolves in about 70 % of ovarian cancer patients and is a major cause of death in this tumor entity. However, it is not well understood, whether and how ADAM17 might contribute to chemo resistance of ovarian cancer. In this study, we identified ADAM17 as an essential upstream regulator of AREG release under chemotherapeutic treatment in ovarian cancer cell lines and patient derived cells. In the majority of ovarian cancer cells cisplatin treatment resulted in enhanced ADAM17 activity, as shown by an increased shedding of AREG. Phorbol 12-myristate 13-acetate (PMA), similarly to cisplatin, mediated AREG shedding and membrane fading of surface ADAM17. Inhibition of ADAM17 with either GW280264X or the anti-ADAM17 antibody D1 (A12) as well as silencing of ADAM17 by siRNA selectively reduced AREG release. Thus, ADAM17 inhibition sensitized cancer cells to cisplatin-induced apoptosis, and significantly reduced cell viability. Based on these findings, we propose that targeting of ADAM17 in parallel to chemotherapeutic treatment suppresses survival pathways and potentially diminish evolving secondary chemo resistance mechanisms. DOI: 10.18632/oncotarget.24682 PMCID: PMC5882316 PID 30026855 29662625 FYN This was clinically relevant as LYN and FYN are also overexpressed in lung cancer clinical specimens. PID 29937990 BUB1 Multiple YAP/TEAD-regulated genes, including AJUBA, ANLN, AREG, ARHGAP29, AURKA, BUB1, CCND1, CDK6, CXCL5, EDN2, DKK1, FOSL1,FOXM1, HBEGF, IGFBP2, JAG1, NOTCH2, RHAMM, RRM2, SERP1, and ZWILCH, are associated with unfavorable survival of PDAC patients. The interaction network of CDCA3, CDCA5, and CDCA8 with their co-expressed genes also revealed that CDCA3 expression was highly correlated with cell cycle related genes such as CCNB2, CDC20, CDKN3, and CCNB1. CDCA5 expression was correlated with BUB1 and TRIP13, while CDCA8 expression was correlated with BUB1 and CCNB1. PID 29682330 29467944 BUB3 PID CENPA PID CKAP5 PID HGF HGF and PlGF were elevated in response to irradiation, while VEGF had a decreasing trend. Within the irradiated population, HGF was also increased in patients diagnosed with radiation cystitis and patients with hematuria. Methods: To address such challenges, we have evaluated therapeutic efficacy of YYB-101, a HGF neutralizing antibody, in a series of primary glioblastoma stem cells (GSCs) both in vitro and in vivo. We also demonstrated HGF-MET signaling axis as a key molecular determinant in GSC invasion and also discovered that a significant association in HGF expression existed between mesenchymal phenotype and immune cell recruitment. Results: Three highly correlated subsets of cyto-/chemokines (Cluster 1: EGF, MIP-1α, MIP-1β; Cluster 2: FGF-2, MIG, IP-10, IL-15, IFN-α, IL-12; and Cluster 3: HGF, IL-6, IL-8) were identified following OT-101 therapy. Suppression of TGF-β signaling by OT-101 led to upregulation of IL-8, IL-15, IP-10, and HGF. However, the c-MET overexpressed and HGF overexpressed cell lines showed moderate dependency on MET pathway. A panel of biomarkers including CEA (carcinoembryonic antigen), CYFRA21-1 (cytokeratin-19 fragment 21-1), CA125 (carbohydrate antigen 125), HGF (hepatocyte growth factor), and NY-ESO-1 (New York esophageal cancer-1 antibody) was measured using immunoassay techniques. PID 30059715 29939324 29785126 29435981 29371783 C7 The C7 pedicle as a superior fixation point in spinal stabilization for spinal metastatic disease. Thind H(1)(2), Fabiano AJ(1)(2). Author information: (1)Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York, USA. (2)Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA. Spinal metastatic disease (SMD) often requires spinal stabilization; however, the cervicothoracic junction can be a challenging area to instrument. The C7 pedicle is able to support pedicle screw fixation in most instances based on morphological features of the vertebra. When the C7 pedicle is used as a superior fixation point, it aligns with the thoracic pedicles below to create a streamlined posterior construct. In this study, patients undergoing posterior stabilization with C7 pedicle superior fixation were examined. One hundred and thirty-nine consecutive spinal operations at a National Cancer Institute designated cancer center were retrospectively reviewed to identify patients who underwent spinal stabilization for SMD with a C7 pedicle screw placed as the superior fixation point of a posterior construct. Three patients were identified who underwent separation surgery for SMD that included posterior spinal stabilization with C7 pedicle screws as the superior fixation point. These findings add to a small but notable number of studies showing the effectiveness of C7 pedicle screws as a superior fixation point in spinal oncology, specifically in metastatic lesions. In our experience the C7 pedicle has provided a useful superior fixation point solution for the posterior stabilization of high thoracic vertebral body metastases. PID 29732436 CSNK2A1 PID CYFIP1 PID ARHGAP9 Silencing ARHGAP9 correlates with the risk of breast cancer and inhibits the proliferation, migration, and invasion of breast cancer. Wang T(1), Ha M(1). Author information: (1)Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China. Breast cancer (BC) is one of the most common malignant tumors in women, and screening relevant genes and markers that are involved in BC tumor genesis and progression is of great value. We previously found that messenger RNA expression of ARHGAP9 was high in BC tissue, but it is unclear whether ARHGAP9 participates in the progression of human BC. In this study, we found that ARHGAP9 expression was correlated with poor patient survival, American Joint Committee on Cancer clinical staging, tumor size, and tumor differentiation. MCF-7 and MDA-MB-231 cells exhibited higher expression of ARHGAP9 than other human BC cell lines (HCC1937, MDA-MB-453, ZR-75-1, and Hs 578T). Knockdown of ARHGAP9 in human BC cells markedly reduced the cell proliferation, migration, and invasive ability of MCF-7 and MDA-MB-231 cells. Furthermore, small interfering RNA (siRNA) of ARHGAP9 also induced G0-G1 cell cycle arrest and apoptosis in MCF-7 and MDA-MB-231 cells. Expressions of cell cycle markers (CDK2 and CCNB1) and invasion-related protein (RhoC and MTA1) were downregulated in siRNA-ARHGAP9-transfected cells. siRNA of ARHGAP9 also inhibited the phosphorylation of mitogen-activated protein kinases in BC cells. In conclusion, the abnormal expression of ARHGAP9 may correlate with the genesis, development, and diagnosis of BC. © 2018 Wiley Periodicals, Inc. DOI: 10.1002/jcb.27127 PID 29905031 NEDD4 PID PTPN18 PID KLC3 PID PSAP PID TRAF2 PID RPF1 PID RIPK2 Interestingly, elevated RIPK2 activity levels were present in a majority of pre-chemotherapy samples from IBC patients at the time of diagnosis to suggest that patients at diagnosis had molecular activation of NF-κB via RIPK2, a phenomenon we define as "molecular inflammation". Surprisingly, chemotherapy did cause a significant increase in RIPK2 activity and thus molecular inflammation suggesting that chemotherapy does not resolve the molecular activation of NF-κB via RIPK2. Indeed, we can demonstrate that RIPK2 activity correlated with advanced tumor, metastasis, and group stage as well as body mass index (BMI) to indicate that RIPK2 might be a useful prognostic marker for IBC and advanced stage breast cancer. DOI: 10.3390/cancers10060184 PMCID: PMC6025367 PID 29874851 CSNK2A2 PID AVP PID GNGT2 PID IAPP PID SDC1 The predicting value of serum SDC1 level has not been evaluated yet. PATIENTS AND METHODS: We assessed the baseline levels of SDC1 in serum samples of 75 patients with CRPC who received docetaxel therapy until the appearance of therapy resistance. Serum SDC1 levels were correlated with clinical outcomes as well as with serum levels of MMP7. RESULTS: Pretreatment SDC1 serum levels were not associated with patients' age, the presence of bone or visceral metastases. In univariable analyses, patients' performance status, the presence of bone or visceral metastases, high pretreatment prostate specific antigen and SDC1 levels were significantly associated with cancer-specific survival. In multivariable analysis patients' performance status (P = 0.005), presence of bone or visceral metastases (P = 0.013) and high SDC1 level (P = 0.045) remained independent predictors of patients' survival. In the patient with available follow-up samples serum SDC1 level increased from 50 to 300ng/ml at radiographic progression. Serum concentrations of SDC1 were correlated with those of MMP7 (r = 0.420, P = 0.006). CONCLUSIONS: Our present results together with currently published data suggest a role for SDC1 shedding in chemotherapy resistance. Determination of serum SDC1 may contribute to the prediction of docetaxel resistance and therefore may help to facilitate clinical decision-making regarding the type and timing of therapy for patients with CRPC. Copyright © 2018 Elsevier Inc. PID 29628317 GNA15 PID GNA14 PID RHOB PID AGT PID ADRA2A PID USP16 PID C6 Mar 11. MeCP2 overexpression inhibits proliferation, migration and invasion of C6 glioma by modulating ERK signaling and gene expression. Sharma K(1), Singh J(1), Frost EE(2), Pillai PP(3). Author information: (1)Division of Neurobiology, Department of Zoology, Faculty of Science, The M. Stable overexpression of MeCP2in C6 glioma cells inhibits proliferation, migration, invasion, and adhesion. Moreover, MeCP2 overexpression inhibits pERKand BDNF expression while inducing GFAP expression in C6 glioma. The intrathecal catheter was located at the level of C6 vertebra. METHODS: A 70-year-old male patient had severe neck pain for 6 weeks because of metastatic mass lesions in C6. Localisation of the carotid artery, internal jugular vein, and trachea had been determined with USG. 3 mL of 2% lidocaine was infiltrated after proceeding a needle from the axis of the trochar to the C6 vertebra corpus. Then C6 VP procedure had been completed without complications. PID 29540297 29369202 28887680 ****2017 SRC Oncotarget. 2017 Dec 20;9(4):4722-4736. doi: 10.18632/oncotarget.23524. eCollection 2018 Jan 12. Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer. McGivern N(1), El-Helali A(1), Mullan P(1), McNeish IA(2), Paul Harkin D(1)(3), Kennedy RD(1)(3), McCabe N(1)(3). Author information: (1)Centre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland, UK. (2)Institute of Cancer Sciences, University of Glasgow, Scotland, UK. (3)Almac Diagnostics, 19 Seagoe Industrial Estate, Craigavon, Northern Ireland, UK. SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease. In this study we aimed to identify mechanisms of resistance to SRC inhibitors in ovarian cancer cells. Furthermore, we demonstrate a synergistic effect of combining SRC and MEK inhibitors in both AZD0530 sensitive and resistant cells, and that MEK inhibition is sufficient to completely resensitize AZD0530 resistant cells. This work provides a preclinical rationale for the combination of SRC and MEK inhibitors in the treatment of ovarian cancer, and also highlights the need for biomarker driven patient selection for clinical trials. DOI: 10.18632/oncotarget.23524 PMCID: PMC5797008 Finally, MYC-driven, BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, including SRC family and c-KIT tyrosine kinases, as well as glucose, glutamine, and serine metabolic pathways. Metastatic involvement of the parotid gland has been reported in gastric cancer patients, but never bilaterally nor in association with the SRC histotype. In the literature, only 3 cases of parotid gland metastases arising from gastric cancer are described - none with a feature of SRC carcinoma. Conclusions To the best of our knowledge, this is the first report of gastric SRC carcinoma with bilateral parotid metastases. In myxoid and round cell liposarcoma (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one of the most activated kinases. The involvement of SRC/FAK activation in FUS-CHOP-mediated invasion was further confirmed using the SRC inhibitor dasatinib, the specific FAK inhibitor PF-573228, and FAK siRNA. In conclusion, radiotherapy could improve survival for RC patients with MAC and SRC, but only for patients in stage II and III. SRC family kinases (SFKs) and HER family ligands promote the nuclear translocation of EGFR. Conclusion: ALB, AKT1, TP53, SRC and MYC are the common genes that play crucial roles in the related biological processes of UC and COAC. PID 29435137 29212027 29192740 29190494 28272410 28049763 29511478 LIG1 PID HDAC7 2017 Mar 15. The expression of HDAC7 in cancerous gastric tissues is positively associated with distant metastasis and poor patient prognosis. Yu Y(1), Cao F(1), Yu X(1), Zhou P(2), Di Q(1), Lei J(1), Tai Y(1), Wu H(1), Li X(1), Wang X(1), Zhang W(3), Li P(4), Li Y(5). Author information: (1)Department of Oncology, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang Rd., 442000, Shiyan, China. (2)Department of Medical Laborotary, The First Affiliated Hospital, Nanchang University, 330006, Nanchang, China. (3)Department of Medical Affairs, Renmin Hospital, Hubei University of Medicine, 442000, Shiyan, China. (4)Cancer Center of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, China. lpd8204@163.com. (5)Department of Oncology, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang Rd., 442000, Shiyan, China. studyong@outlook.com. PURPOSE: To characterize the expression patterns of HDAC7 in patients with gastric cancer and evaluate the prognostic value of HDAC7 in gastric cancer. METHODS: The expression of histone deacetylase 7 (HDAC7) was detected in paraffin-embedded gastric cancer samples from 86 patients by immunohistochemistry, and the differences in the expression of HDAC7 between cancerous and corresponding adjacent noncancerous tissues were compared using the Wilcoxon matched-pairs signed rank test. The correlation between HDAC7 expression and Ki-67 expression or clinicopathologic characteristics was evaluated using a Spearman rank correlation test. Prognostic outcomes that correlated with HDAC7 were examined using a Kaplan-Meier analysis and Cox proportional hazards model. Moreover, the effects of HDAC7 on the proliferation, migration and invasion of gastric cancer cells were investigated in vitro using human gastric carcinoma AGS cells. RESULTS: We found that HDAC7 was downregulated in cancerous gastric tissues (P = 0.0019). However, the expression of HDAC7 in cancerous gastric tissues positively correlated with Ki-67 expression (P = 0.0325) and distant metastasis (P = 0.020). Moreover, overall survival was shorter for patients expressing higher levels of HDAC7 in cancerous tissues (P = 0.042). Mechanistically, the disruption of the HDAC7 gene attenuated the capacity of cell growth, migration and invasion and induced G0/G1 arrest in AGS cells. Conversely, forced ovperexpression of HDAC7 promoted cell growth, migration and invasion and G1/S transition in AGS cells. CONCLUSIONS: These results indicate that high HDAC7 expression in cancerous gastric tissues correlates with distant metastasis and predicts a poor prognosis for patients with gastric cancer. DOI: 10.1007/s12094-017-1639-9 PID 28299580 MIF DEX (1 mg/kg) also reduced the immunoexpression of cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-2, transforming growth factor (TGF)-β, MIF, Smad 2/3, Smad 2/3 phosphorylated and NFκB p65 in the jugal mucosa. RESULTS: The final classifier was a logistic regression using ten predictors: eight proteins (A1AG, CEA, CO9, DPPIV, MIF, PKM2, SAA, TFRC), age, and gender. Levels of sTNF-r1, IL-6, IL-18, MIF, MCP-1, TGF-β1, IL-1ra, and C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR) were elevated; IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12(p70), interferon-γ, MIP-1α, and TNF-α were below the level of detection. Bevacizumab-resistant patient glioblastomas and both novel xenograft models of resistance had less MIF than bevacizumab-naive tumors, and harbored more M2/protumoral macrophages that specifically localized to the tumor edge. Xenografts expressing MIF-shRNA grew more rapidly with greater angiogenesis and had macrophages localizing to the tumor edge which were more prevalent and proliferative, and displayed M2 polarization, whereas bevacizumab-resistant xenografts transduced to upregulate MIF exhibited the opposite changes. Bone marrow-derived macrophage were polarized to an M2 phenotype in the presence of condition-media derived from bevacizumab-resistant xenograft-derived cells, while recombinant MIF drove M1 polarization. Two mechanisms of bevacizumab-induced MIF reduction were identified: (1) bevacizumab bound MIF and blocked MIF-induced M1 polarization of macrophages; and (2) VEGF increased glioma MIF production in a VEGFR2-dependent manner, suggesting that bevacizumab-induced VEGF depletion would downregulate MIF. Site-directed biopsies revealed enriched MIF and VEGF at the enhancing edge in bevacizumab-naive patients. This MIF enrichment was lost in bevacizumab-resistant glioblastomas, driving a tumor edge M1-to-M2 transition. Thus, bevacizumab resistance is driven by reduced MIF at the tumor edge causing proliferative expansion of M2 macrophages, which in turn promotes tumor growth. DOI: 10.1038/onc.2017.1 PMCID: PMC5491354 Elevated expression of CXCL2 and MIF and an increased number of CD33+ MDSCs were detected in BC tissues, and these increases were significantly associated with advanced disease stage and poor patient prognosis (P<0.01). A positive association was observed between CXCL2 or MIF expression and the number of tumor-infiltrating CD33+ MDSCs (P<0.01). PID 29059216 28769740 28542626 28218903 27721403 TUBB PID NET1 PID PAK2 PID PAK1 Tissue microarrays were constructed and immunohistochemical stains were performed for PAK1, PAK4, hENT1, and TS. PAK1, hENT1, and TS expression status did not have significant influences on patient survival. PID 28556956 CLASP1 PID BRCC3 PID RAC3 PID PAK3 PID E2F1 ANXA3 small interfering RNA (siRNA) also reduced the expression of cycle-dependent kinase protein and increased the expression of E2F1 and p27 proteins compared with control siRNA. PTEN-4A physically interacted with the transcription factor E2F1 and associated with chromatin at gene promoters with E2F1 DNA-binding sites, a likely mechanism for its transcriptional suppression function. Abbreviations AKT V-Akt Murine Thymoma Viral Oncogene CA Cancer adjacent CDK1 Cyclin dependent kinase 1 CENPC-C Centromere Protein C ChIP Chromatin Immunoprecipitation co-IP Co-immunoprecipitation COSMIC Catalog of Somatic Mutations In Cancer CREB cAMP Responsive Element Binding Protein C-tail Carboxy terminal tail E2F1 E2F Transcription Factor 1 ECIS Electric Cell-substrate Impedance Sensing EGFR Epidermal Growth Factor Receptor GSI Gamma Secretase Inhibitor HDAC1 Histone Deacetylase 1 HP1 Heterochromatin protein 1 KAP1/TRIM28 KRAB-Associated Protein 1/Tripartite Motif Containing 28 MAF1 Repressor of RNA polymerase III transcription MAF1 homolog MCM2 Minichromosome Maintenance Complex Component 2 miRNA micro RNA MTF1 Metal-Regulatory Transcription Factor 1 PARP Poly(ADP-Ribose) Polymerase PD-1 Programmed Cell Death 1 PD-L1 Programmed Cell Death 1 Ligand 1 PI3K Phosphatidylinositol-4,5-Bisphosphate 3-Kinase PLK Polo-like Kinase pPTEN Phosphorylated PTEN PTEN Phosphatase and Tensin Homolog deleted on chromosome ten PTM Post Translational Modification Rad51 RAD51 Recombinase Rad52 RAD52 Recombinase RPA1 Replication protein A SILAC Stable Isotope Labeling with Amino Acids in Cell Culture SRF Serum Response Factor TKI Tyrosine Kinase inhbitors TMA Tissue Microarray TOP2A DNA Topoisomerase 2A. DOI: 10.1080/15384101.2017.1388970 eCollection 2017. Prognostic value of E2F1 in rectal cancer. Uzer H(1), Akyıldız H(1), Sözüer E(1), Akcan A(1), Öz B(1). Author information: (1)Department of General Surgery, Erciyes University School of Medicine, Kayseri, Turkey. OBJECTIVE: To evaluate whether E2F transcription factor 1 is a potential prognostic marker in patients with rectal cancer. 10.1016/j.euf.2017.02.009. [Epub ahead of print] E2F1 Signalling is Predictive of Chemoresistance and Lymphogenic Metastasis in Penile Cancer: A Pilot Functional Study Reveals New Prognostic Biomarkers. Fenner F(1), Goody D(2), Protzel C(3), Erbersdobler A(4), Richter C(2), Hartz JM(2), Naumann CM(5), Kalthoff H(6), Herchenröder O(2), Hakenberg OW(7), Pützer BM(8). Author information: (1)Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Centre, Rostock, Germany; Urology Department, University of Rostock, Rostock, Germany. (2)Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Centre, Rostock, Germany. (3)Urology Department, University of Rostock, Rostock, Germany. (4)Institute of Pathology, University Medicine Rostock, Rostock, Germany. (5)Department of Urology and Paediatric Urology, University Hospital Schleswig-Holstein, Kiel, Germany. (6)Division Molecular Oncology, Institute for Experimental Cancer Research, Cancer Centre North, University Hospital Schleswig-Holstein, Kiel, Germany. (7)Urology Department, University of Rostock, Rostock, Germany. Data were further validated in E2F1 transcription factor knockdown and overexpression experiments. We quantified E2F1 transcript levels in a set of nonmetastatic tumours (NM), metastasised primary tumours (PT), and lymph node metastases (M) from 24 patients. E2F1 immunohistochemistry was performed in another set of 13 PC biopsies. RESULTS AND LIMITATIONS: In cell lines established from lymph node metastases, E2F1 was more abundantly expressed, pRB was inactivated, and CDK2, CDK4, and cyclins D and E were elevated in comparison to cells from primary PC. Overexpression of E2F1 enhanced migratory capacity and lymphatic endothelial tubule formation, while depletion reduced invasiveness and increased chemosensitivity. VEGFR-3 and VEGF-C and mesenchymal markers were upregulated by high E2F1. E2F1 was clearly upregulated in infiltrative and metastatic primary tumours and metastases (NM vs PT, p<0.05; NM vs M, p<0.0005). E2F1 Quick scores increased from grade I to grade III tumours. CONCLUSIONS: E2F1 is a driver of invasion and lymphatic dissemination and promotes chemoresistance. RB1 interacted with E2F1 and both could mediate EMT process in NSCLC. E2F1 is a transcription factor that plays an important role in regulating cell growth, differentiation, apoptosis and response to DNA damage. We analyzed E2F1 CNVs in 261 cases with TGCT and 165 controls. We found no CNVs in controls, but 17/261 (6.5%) cases showed duplications in E2F1 Blot analysis demonstrated higher E2F1 expression in testicular samples of TGCT cases with three copies of the gene. Furthermore, we observed higher phosphorylation of Akt and mTOR in samples with E2F1 duplication. Interestingly, normal, non-tumoral testicular tissue in patient with E2F1 duplication showed lower expression of E2F1 and lower AKT/mTOR phosphorylation with respect to adjacent tumor tissue. Furthermore, increased expression of E2F1 obtained in vitro in NTERA-2 testicular cell line induced increased AKT/mTOR phosphorylation. This study suggests for the first time an involvement of E2F1 CNVs in TGCT susceptibility and supports previous preliminary data on the importance of AKT/mTOR signaling pathway in this cancer. © 2017 Society for Endocrinology. DOI: 10.1530/ERC-16-0514 Chromatin immunoprecipitation analysis indicated that E6AP reduced the amount of E2F1 at the CDC6 promoter. Epub 2017 Jan 9. KLF4 is regulated by RAS/RAF/MEK/ERK signaling through E2F1 and promotes melanoma cell growth. Riverso M(1), Montagnani V(1), Stecca B(1)(2). Author information: (1)Core Research Laboratory-Istituto Toscano Tumori, Florence, Italy. (2)Department of Oncology, Careggi University Hospital, Florence, Italy. Melanoma is the most lethal form of skin cancer and treatment of metastatic melanoma remains challenging. We find that the RAS/RAF/MEK/ERK signaling positively modulates KLF4 expression through the transcription factor E2F1, which directly binds to KLF4 promoter. PID 29217453 29108454 28944330 28753861 28716024 28104681 28074012 28068326 GNAO1 PID TUBB2A Nonetheless, SNPs in CYP2C8, CYP3A4, ARHGEF10, EPHA and TUBB2A genes (taxanes), FARS2, ACYP2 and TAC1 (oxaliplatin), and CEP75 and CYP3A5 (vincristine) are of potential interest. PID 29198326 CDK2 RESULTS AND LIMITATIONS: In cell lines established from lymph node metastases, E2F1 was more abundantly expressed, pRB was inactivated, and CDK2, CDK4, and cyclins D and E were elevated in comparison to cells from primary PC. KIF15 upregulated cyclin D1, CDK2, and phospho-RB and also promoted G1/S transition in pancreatic cancer cells. Detection of cell cycle marker expression showed that CDKN3 knockdown promotes cell cycle arrest by decreasing the expression of CDK2, CDC25A, CCNB1, and CCNB2 in human gastric cancer cells. PID 28753861 28595260 27983933 USP21 PID KIF2A PID HDAC9 Epub 2017 Mar 7. Downregulation of miR-377 Promotes Oral Squamous Cell Carcinoma Growth and Migration by Targeting HDAC9. Rastogi B(1), Kumar A(2), Raut SK(2), Panda NK(1), Rattan V(3), Joshi N(2), Khullar M(2). Author information: (1)a Department of Otolaryngology and Head and Neck Surgery , Postgraduate Institute of Medical Education and Research , Chandigarh , India. (2)b Department of Experimental Medicine and Biotechnology , Postgraduate Institute of Medical Education and Research , Chandigarh , India. (3)c Department of Oral Health Sciences Centre , Postgraduate Institute of Medical Education and Research , Chandigarh , India. microRNAs are the post-transcriptional regulators implicated in the initiation and progression of various cancer types, including oral squamous cell carcinoma (OSCC). We identified HDAC9 as a target of miR-377 and found miR-377 to regulate HDAC9 and its pro-apoptotic target, NR4A1/Nur77. Our findings show that miR-377 targets HDAC9 pathway in OSCC, suggesting that miR-377-HDAC9 axis may provide a novel therapeutic target for OSCC therapy. DOI: 10.1080/07357907.2017.1286669 GEP revealed upregulation of MAPK10, HELIOS, HDAC9, and FYN, as well as downregulation of SH3BP5 and LCK. PID 28267394 27993968 KLC2 PID DYNLL1 PID TUBB1 PID ATF2 PID METAP2 PID LRIG1 PID PARD3 PID PKN1 The overlap of changed genes between the cell lines was small (149), but the involved pathways in the reactome and GO- analyses showed a high overlap with DNA methylation, cell cycle, SIRT1, PKN1 pathway, DNA repair and oxidative stress as well known cancer-associated representatives. PID 29348853 PKN2 PID PRICKLE1 PID PTPRU PID STK4 PID PAN2 PID ADCY3 PID HIST3H3 PID HK2 In the present study, we studied the tumorigenic role of HK2 in glioma, and clarified the mechanism of miR-218 induced HK2 regulation in glioma development. The HK2 expression in patient derived glioma and non neoplastic brain tissue was quantified. The HK2 silenced U87 and U251 cell lines were assessed for their proliferation, migration and invasive potential in vitro, while the tumor forming potential of U87 cells was evaluated in vivo. The HK2 expression in (a) lentivirus-infected, miR-218 overexpressing and (b) shRNA mediated Bmi1 silenced U87 and U251 glioma cell lines were quantified. The HK2 expression was significantly increased in glioma tissues comparing with the non neoplastic brain tissues and was positively correlated with the glioma grade. Silencing HK2 in glioma cell lines significantly decreased their proliferation, migration, invasion and tumorigenic abilities. Although, overexpression of miR-218 significantly downregulated the HK2 expression, luciferase reporter assay failed to show HK2 as the direct target of miR-218. A direct correlation, however, was observed between HK2 and Bmi-1, the direct target of miR-218. Taken together, our findings confirmed the tumorigenic activity of HK2 in glioma, and the involvement of the miR218/Bmi1 pathway in the regulation of its expression. DOI: 10.1371/journal.pone.0189353 PMCID: PMC5722312 Mechanistically, YAP promotes the expression of BCAR4, which subsequently coordinates the Hedgehog signaling to enhance the transcription of glycolysis activators HK2 and PFKFB3. Our data show that miR-143 complementary pairs to the 3'-UTR of HK2 in oral cancer cells, leading to the inhibition of glycolysis in vitro and in vivo Moreover, knockdown of HK2 by siRNA in oral cancer cells inhibited glucose metabolism, proliferation and migration. Recovery of glucose metabolism by overexpression of HK2 in miR-143 overexpressing cells restores the cell migration and proliferation, suggesting that the miR-143-mediated cancer suppression is through the direct inhibition of HK2. In summary, the present studies highlight miR-143 as a tumor suppressor in OSCC by the suppression of cell migration, glucose metabolism and proliferation through directly targeting HK2, rendering miR-143 a therapeutic strategy for the treatment of clinical OSCC patients. © 2017 The Author(s). DOI: 10.1042/BSR20160404 PMCID: PMC5463264 HK2 was most highly expressed in PDAC metastases, suggesting a link between HK2 and aggressive tumor biology. In support of this we found HK2 expression to be associated with shorter overall survival in PDAC patients undergoing curative surgery. Transient and stable knockdown of HK2 in primary PDAC cell lines decreased lactate production, anchorage independent growth (AIG) and invasion through a reconstituted matrix. Conversely, stable overexpression of HK2 increased lactate production, cell proliferation, AIG and invasion. Stable knockdown of HK2 decreased primary tumor growth in cell line xenografts and decreased incidence of lung metastasis after tail vein injection. Gene expression analysis of tumors with decreased HK2 expression showed alterations in VEGF-A signaling, a pathway important for angiogenesis and metastasis, consistent with a requirement of HK2 in promoting metastasis. Overall our data provides strong evidence for the role of HK2 in promoting PDAC disease progression, suggesting that direct inhibition of HK2 may be a promising approach in the clinic. DOI: 10.18632/oncotarget.9760 PMCID: PMC5593546 PID 29220380 28963395 28174335 28915575 PPP2R5E PID PPP2R5A PID PRKCA PID ADAM17 Results: More specifically, lowered expression of ADAM17 correlated with good prognosis in KICH, KIRC and KIRP (HR = 7.79, p = 0.03; HR = 3.98, p = 0.051; HR = 11.24, p < 0.001, respectively). Nivolumab effectively inhibit platinum-resistant ovarian cancer cells via induction of cell apoptosis and inhibition of ADAM17 expression. Sun LM(1), Liu YC, Li W, Liu S, Liu HX, Li LW, Ma R. Author information: (1)Department of Gynecological Oncology, Third Affiliated Hospital of Harbin Medical University, Heilongjiang, Harbin, China. kjwoo080@sina.com. OBJECTIVE: Nivolumab is an anti-PD-1 (anti-programmed death-1) monoclonal antibody. Additionally, the expression levels of ADAM17 were significantly decreased in a dose-dependent manner in PROC cells, which were treated with nivolumab. CONCLUSIONS: Therefore, all the results demonstrated that the combined treatment with nivolumab and cisplatin effectively inhibited PROC cells via induction of cell apoptosis and inhibition of ADAM17 expression. The A Disintegrin and Metalloproteinases ADAM10 and ADAM17 are among the most prominent sheddases, being widely expressed in many tissues, frequently overexpressed in cancer, and promiscuously cleaving diverse substrates. 2016 Aug 19. Metalloproteinases ADAM10 and ADAM17 Mediate Migration and Differentiation in Glioblastoma Sphere-Forming Cells. Siney EJ(1)(2)(3), Holden A(4), Casselden E(4), Bulstrode H(5), Thomas GJ(6), Willaime-Morawek S(4). Author information: (1)Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK. ejs304@soton.ac.uk. (2)Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK. ejs304@soton.ac.uk. (3)Southampton General Hospital, LF51, South Laboratory Block, Southampton, SO16 6YD, UK. ejs304@soton.ac.uk. (4)Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK. (5)Wessex Neurological Centre, University Hospital Southampton, Southampton, SO16 6YD, UK. (6)Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK. Glioblastoma is the most common form of primary malignant brain tumour. We have focused on the role of two closely related metalloproteinases ADAM10 and ADAM17 due to their high expression in glioblastoma and GSCs and their ability to activate cytokines and growth factors. Here, we report that ADAM10 and ADAM17 inhibition selectively increases GSC, but not neural stem cell, migration and that the migrated GSCs exhibit a differentiated phenotype. Our results suggest that therapies against ADAM10 and ADAM17 may promote cancer stem cell migration away from the tumourigenic niche resulting in a differentiated phenotype that is more susceptible to treatment. DOI: 10.1007/s12035-016-0053-6 PMCID: PMC5443867 PID 29181054 28387913 27895032 27541285 FYN GEP revealed upregulation of MAPK10, HELIOS, HDAC9, and FYN, as well as downregulation of SH3BP5 and LCK. PID 27993968 BUB1 In total, 59 kinases associated genes were found over-expressed in HCC, including TTK, MELK, BUB1, NEK2, BUB1B, AURKB, PLK1, CDK1, PKMYT1, PBK, etc. Our analysis showed that MMP2, COL3A1, COL1A2, FBN1, COL5A1, COL5A2, and AEBP1 are top hub genes related to stage, while CDK1, BUB1, BUB1B, BIRC5, AURKB, CENPA, and CDC20 are top hub genes related to grade. PID 29025594 28562334 BUB3 Deleterious germline mutations were also found in BUB1B (1) and BUB3 (1). PID 28767289 CENPA Our analysis showed that MMP2, COL3A1, COL1A2, FBN1, COL5A1, COL5A2, and AEBP1 are top hub genes related to stage, while CDK1, BUB1, BUB1B, BIRC5, AURKB, CENPA, and CDC20 are top hub genes related to grade. PID 28562334 CKAP5 PID HGF By contrast, these CARs did not mediate T-cell activation upon engagement of other HGF binding partners, namely CD44v6 or heparan sulfate proteoglycans, including Syndecan-1. Secondary objectives included safety, pharmacokinetics, response and potential biomarkers of response including EGFR, KRAS genotype, MET, AXL expression, and circulating HGF levels. HGF levels), pro-inflammatory/ pro-cachexia (e.g. MET, the HGF receptor, is encoded by the MET proto-oncogene that may be activated by mutation or amplification. IL-6 and HGF that were selected as potential paracrine mediators using cytokine array induced 17βHSD2, 17βHSD5, and 5α-Reductase1 expression. CONCLUSIONS: Results of our present study suggest that both IL-6 and HGF derived from CAFs could contribute to the intratumoral androgen metabolism in ER-negative BC patients. DOI: 10.1007/s10549-017-4464-5 Here, we show that a fraction of murine effector CTLs expresses the HGF receptor c-Met (c-Met+ CTLs). Furthermore, HGF directly restrains the cytolytic function of c-Met+ CTLs in cell-mediated cytotoxicity reactions in vitro and in vivo and abrogates T-cell responses against metastatic melanoma in vivo Finally, we establish in three murine tumor settings and in human melanoma tissues that c-Met+ CTLs are a naturally occurring CD8+ T-cell population. Typical paracrine HGF/Met signaling is regulated by HGF activation at target cell surfaces, HGF binding-induced receptor activation, internalization and degradation. We review here HGF and Met structure and function, basic properties of HGF/Met pathway antagonists now in clinical development, and recent clinical trial results. MET-driven PRCC was defined as any of the following: chromosome 7 copy gain, focal MET or HGF gene amplification, or MET kinase domain mutations. RESULTS: Expression of E-cadherin, MMP7, HGF, and CD133 at the deep invasive front was associated with the absence of lymph node metastasis (P=0.013, 0.018, <0.001, and 0.026, respectively). Presence of diffuse-type component, lymphatic invasion, and lack of expression of HGF and CD133 at the deep invasive front were independent predictive markers of lymph node metastasis (P=0.019, <0.001, 0.015, and 0.047, respectively). CONCLUSIONS: Lymph node metastasis is strongly associated with expression status of HGF and CD133 at the deep invasive front, suggesting the usefulness of these proteins as independent predictive markers of lymph node metastasis in early gastric cancer. Copyright © 2017 Elsevier GmbH. Furthermore, exclusively in co-culture with ADSCs, the different BRCAs were exposed to several important tumor-modulating proteins, such as CCL2, HGF, or interleukins. Here, we develop findings that the growth factor HGF promotes CSC sphere formation in NSCLC cell populations. In patient-derived sphere-forming assays (PD-SFA) with HGF, CD49f and CD104 were defined as novel markers of lung CSC (LCSC). Epub 2017 Mar 24. MET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of an HGF Antibody. Farrell PJ(1), Matuszkiewicz J(2), Balakrishna D(2), Pandya S(2), Hixon MS(2), Kamran R(2), Chu S(3), Lawson JD(4), Okada K(5), Hori A(5), Mizutani A(5), Iwata H(5), de Jong R(2), Hibner B(6), Vincent P(2). Author information: (1)Department of Biological Sciences, Takeda California, San Diego, California. pw2h@att.net. (2)Department of Biological Sciences, Takeda California, San Diego, California. (3)Department of Chemistry, Takeda California, San Diego, California. (4)Department of Computational Sciences and Crystallography, Takeda California, San Diego, California. (5)Pharmaceutical Research Division, Takeda Pharmaceutical Companies Ltd, Shonan, Japan. (6)Oncology Biology, Takeda Boston, Cambridge, Massachusetts. Receptor tyrosine kinase therapies have proven to be efficacious in specific cancer patient populations; however, a significant limitation of tyrosine kinase inhibitor (TKI) treatment is the emergence of resistance mechanisms leading to a transient, partial, or complete lack of response. We evaluated the combined action of simultaneously neutralizing HGF ligand and inhibiting MET kinase activity in two cancer xenograft models that exhibit autocrine HGF/MET activation. These results hold promise that dual targeting of HGF and MET by combining extracellular ligand inhibitors with intracellular MET TKIs could be an effective intervention strategy for cancer patients who have acquired resistance that is dependent on total MET protein. The patients who have demonstrated response, prolonged clinical benefit and tolerability, and with anti-VEGF therapy are likely to benefit from continued antiangiogenic activity combined with MET and HGF inhibition with cabozantinib at progression. Mar 9. 89Zr-DFO-AMG102 Immuno-PET to Determine Local Hepatocyte Growth Factor Protein Levels in Tumors for Enhanced Patient Selection. Price EW(1), Carnazza KE(1), Carlin SD(1), Cho A(1), Edwards KJ(1), Sevak KK(1), Glaser JM(1), de Stanchina E(2), Janjigian YY(3), Lewis JS(4)(5). Author information: (1)Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. (2)Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York. (3)Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York; and. (4)Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York lewisj2@mskcc.org. (5)Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York. The hepatocyte growth factor (HGF) binding antibody rilotumumab (AMG102) was modified for use as a 89Zr-based immuno-PET imaging agent to noninvasively determine the local levels of HGF protein in tumors. Because recent clinical trials of HGF-targeting therapies have been largely unsuccessful in several different cancers (e.g., gastric, brain, lung), we have synthesized and validated 89Zr-DFO-AMG102 as a companion diagnostic for improved identification and selection of patients having high local levels of HGF in tumors. To date, patient selection has not been performed using the local levels of HGF protein in tumors. PET imaging, biodistribution, autoradiography and immunohistochemistry, and ex vivo HGF ELISA experiments were performed on murine xenografts of U87MG (HGF-positive, MET-positive) and MKN45 (HGF-negative, MET-positive) and 4 patient-derived xenografts (MET-positive, HGF unknown). Similar experiments performed in 4 different gastric cancer patient-derived xenograft models showed low uptake of 89Zr-DFO-AMG102 (∼4-7 %ID/g), which corresponded with low HGF levels in these tumors (ex vivo ELISA). Autoradiography, immunohistochemical staining, and HGF ELISA assays confirmed that elevated levels of HGF protein were present only in U87MG tumors and that 89Zr-DFO-AMG102 uptake was closely correlated with HGF protein levels in tumors. Conclusion: The new immuno-PET imaging agent 89Zr-DFO-AMG102 was successfully synthesized, radiolabeled, and validated in vitro and in vivo to selectively accumulate in tumors with high local levels of HGF protein. These results suggest that 89Zr-DFO-AMG102 would be a valuable companion diagnostic tool for the noninvasive selection of patients with elevated local concentrations of HGF in tumors for planning any HGF-targeted therapy, with the potential to improve clinical outcomes. © 2017 by the Society of Nuclear Medicine and Molecular Imaging. DOI: 10.2967/jnumed.116.187310 PMCID: PMC5577625 Hepatocyte growth factor (HGF)-induced phosphorylation of the kinase AKT was specifically promoted by NRP2b, whereas inhibiting the HGF receptor MET attenuated NRP2b-dependent cell migration. This study, for the first time, explores patient characteristics and temporal trends associated with HGF utilization among elderly lung cancer patients receiving chemotherapy. Temporal variations were most predictive of HGF utilization, with an increase from 2.6% in 1992 to 47.3% in 2009 for CSFs and 1.3% to 30.5% for ESAs. Higher chemotherapy-based risk profiles increased the odds of HGF receipt 2 to 3 times (P<0.0001). Even after controlling for relevant clinical characteristics, unexplained sociodemographic associations persisted, suggesting lack of compliance with HGF guidelines. CONCLUSIONS: There has been a significant increase in the use of HGFs over time. Although chemotherapy-based risk profiles were significant predictors of HGF receipt, the study results suggest possible lack of compliance with treatment guidelines, which should be investigated. PID 29209570 29050231 28938541 28836864 28831645 28751311 28673936 28644771 28595915 28545495 28416482 28341789 28286925 28280216 28096505 25068470 C7 PID CSNK2A1 High expression of the genes SPP1 and CSNK2A1 (encoding Osteopontin and CK2α respectively) correlated with poor prognosis while high expression of DEFB1 (encoding β-Defensin) correlated with better prognosis. PID 28975890 CYFIP1 PID ARHGAP9 PID NEDD4 PID PTPN18 PID KLC3 PID PSAP Although in situ lesion could not be discovered, positive immunostainings for Nkx3.1, PSAP, and androgen receptor in the remaining paraurethral glands around the tumor indirectly but strongly suggest that the tumor had originated from Skene's gland. PID 28872768 TRAF2 PID RPF1 PID RIPK2 PID CSNK2A2 PID AVP MATERIALS AND METHODS: Four patients (3 males, 1 female; median age 69 years) with locally advanced pancreatic body cancer underwent preoperative CHA embolization with AVP. CONCLUSIONS: AVP application is feasible and safe as an embolic procedure for preoperative CHA embolization of DP-CAR. DOI: 10.1007/s00270-016-1509-9 PID 27858118 GNGT2 PID IAPP PID SDC1 PID GNA15 PID GNA14 PID RHOB Comparison with muscle-invasive bladder cancer mutation profiles revealed lower overall mutation rates and more frequent mutations in RHOB and chromatin modifier genes. The RAS-related GTPase RHOB confers resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer via an AKT-dependent mechanism. Calvayrac O(1)(2), Mazières J(3)(2)(4), Figarol S(1), Marty-Detraves C(1), Raymond-Letron I(5), Bousquet E(4), Farella M(1)(6), Clermont-Taranchon E(7), Milia J(2)(4), Rouquette I(7), Guibert N(1)(4), Lusque A(8), Cadranel J(9), Mathiot N(9), Savina A(10), Pradines A(1)(6), Favre G(3)(2)(6). Author information: (1)Inserm, Centre de Recherche en Cancérologie de Toulouse, CRCT UMR-1037, Toulouse, France. (2)Université Paul Sabatier, Toulouse, France. (3)Inserm, Centre de Recherche en Cancérologie de Toulouse, CRCT UMR-1037, Toulouse, France mazieres.j@chu-toulouse.fr favre.gilles@iuct-oncopole.fr. (4)CHU Toulouse, IUCT-Rangueil-Larrey, Service de Pneumologie, Toulouse, France. (5)Laboratoire d'Histopathologie, UPS-INP-ENVT, UMS006, Université de Toulouse, Toulouse, France. (6)Laboratoire de Biologie Médicale Oncologique, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France. (7)Departement d'Anatomo-Cytopathologie, CHU de Toulouse, IUCT-Oncopole, Toulouse, France. (8)Institut Claudius Regaud, IUCT-Oncopole, Bureau des Essais Cliniques, Cellule Biostatistiques, Toulouse, France. (9)Sorbonne Universités UPMC Univ. RHOB GTPase is a critical player in both lung carcinogenesis and the EGFR signaling pathway; therefore, we hypothesized that it could play a role in the response to EGFR-TKI In a series of samples from EGFR-mutated patients, we found that low RHOB expression correlated with a good response to EGFR-TKI treatment while a poor response correlated with high RHOB expression (15.3 versus 5.6 months of progression-free survival). Moreover, a better response to EGFR-TKI was associated with low RHOB levels in a panel of lung tumor cell lines and in a lung-specific tetracycline-inducible EGFRL858R transgenic mouse model. High RHOB expression was also found to prevent erlotinib-induced AKT inhibition in vitro and in vivo Furthermore, a combination of the new-generation AKT inhibitor G594 with erlotinib induced tumor cell death in vitro and tumor regression in vivo in RHOB-positive cells. Our results support a role for RHOB/AKT signaling in the resistance to EGFR-TKI and propose RHOB as a potential predictor of patient response to EGFR-TKI treatment. © 2016 The Authors. PID 29136510 28003335 AGT The single nucleotide polymorphism rs5186 (A1166C) in AGT R1 gene is located in 3' untranslated region (UTR) of the gene, while polymorphism rs1799998 (T -344 C) in CYP11B2 gene is located in the promoter region of the gene. Dd and dd for AGT R1 and patients with genotype HH vs. AGT R1 gene polymorphism did not show any association with studied variables. PID 28601126 ADRA2A PID USP16 PID C6 METHODS: A 70-year-old male patient had severe neck pain for 6 weeks because of metastatic mass lesions in C6. Localisation of the carotid artery, internal jugular vein, and trachea had been determined with USG. 3 mL of 2% lidocaine was infiltrated after proceeding a needle from the axis of the trochar to the C6 vertebra corpus. Then C6 VP procedure had been completed without complications. PID 28887680 ****2016 SRC A cohort of 256 patients with early gastric SRC at our center between January 2002 and December 2015 were retrospectively reviewed. Based on the nomogram, treatment algorithm for early gastric SRC was proposed to assist clinicians in making better decisions. We developed a nomogram predicting risk of LNM for early gastric SRC, which should be helpful for patient counseling and surgical decision-making. DOI: 10.1097/MD.0000000000005393 PMCID: PMC5120931 Pharmacological or pharmacogenetic inhibition of TGFBR1 blocked growth promotion and phosphorylation of SRC, which is frequently associated with vemurafenib-resistance mechanisms. LYN expression predicts the response to dasatinib in a subpopulation of lung adenocarcinoma patients. Kim YJ(1), Hong S(2), Sung M(1), Park MJ(2), Jung K(1)(3), Noh KW(1)(3), Oh DY(1)(3), Lee MS(1)(3), Oh E(1)(3), Shin YK(2)(4), Choi YL(1)(3)(5). Author information: (1)Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. (2)Laboratory of Molecular Pathology and Cancer Genomics, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea. (3)Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea. (4)The Center for Anti-cancer Companion Diagnostics, Bio-MAX/N-Bio, Seoul National University, Seoul, Korea. (5)Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Therapies targeting SRC family kinases (SFKs) have shown efficacy in treating non-small cell lung cancer (NSCLC). Additionally, we identified the SFKs SRC and YES as candidate dasatinib targets in LYN-negative ADC cell lines. Debio 0617B Inhibits Growth of STAT3-Driven Solid Tumors through Combined Inhibition of JAK, SRC, and Class III/V Receptor Tyrosine Kinases. Murone M(1), Vaslin Chessex A(2), Attinger A(2), Ramachandra R(3), Shetty SJ(3), Daginakatte G(3), Sengupta S(3), Marappan S(3), Dhodheri S(3), Rigotti S(2), Bachhav Y(2), Brienza S(2), Traxler P(2), Lang M(2), Aguet M(4), Zoete V(5), Michielin O(5), Nicholas C(6), Johnson FM(7), Ramachandra M(3), McAllister A(2). Author information: (1)Debiopharm International S.A., Lausanne, Switzerland. mmurone@adipogen.com. (2)Debiopharm International S.A., Lausanne, Switzerland. (3)Aurigene Discovery Technologies, Bangalore, Karnataka, India. (4)Swiss Federal Institute of Technology, Lausanne, Switzerland. (5)Swiss Institute of Bioinformatics, Lausanne, Switzerland. (6)Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. (7)Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Tumor survival, metastases, chemoresistance, and escape from immune responses have been associated with inappropriate activation of STAT3 and/or STAT5 in various cancers, including solid tumors. Debio 0617B has been developed as a first-in-class kinase inhibitor with a unique profile targeting phospho-STAT3 (pSTAT3) and/or pSTAT5 in tumors through combined inhibition of JAK, SRC, ABL, and class III/V receptor tyrosine kinases (RTK). High-throughput in vitro drug screening demonstrated that dasatinib, a SRC inhibitor, and PKI-587, a dual PI3K/mTOR inhibitor, exhibited targeted anti-proliferative and pro-apoptotic effects against BD-138T PDCs. Using established patient-derived xenograft models that successfully retain the genomic and molecular characteristics of the parental tumor, we confirmed that these anti-tumor responses occurred through the inhibition of SRC and PI3K/AKT/mTOR signaling pathways. Targeting synthetic lethality between the SRC kinase and the EPHB6 receptor may benefit cancer treatment. Paul JM(1), Toosi B(2), Vizeacoumar FS(2), Bhanumathy KK(2), Li Y(3)(4)(5), Gerger C(2), El Zawily A(2)(6), Freywald T(7), Anderson DH(7), Mousseau D(8), Kanthan R(2), Zhang Z(3)(4), Vizeacoumar FJ(2)(7), Freywald A(2). Author information: (1)Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada. (2)Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada. (3)Department of Computer Science, University of Toronto, Toronto, ON, M5S 3G4, Canada. (4)The Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada. (5)Present address: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. (6)Faculty of Science, Damanhour University, Damanhour, 22516, Egypt. (7)Cancer Research, Saskatchewan Cancer Agency, Saskatoon, SK, S7N 5E5, Canada. (8)Cell Signaling Laboratory, Neuroscience Cluster, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada. Application of tumor genome sequencing has identified numerous loss-of-function alterations in cancer cells. In our work, we used a genome-wide SL screen combined with expression and interaction network analyses, and identified the SRC kinase as a SL partner of EPHB6 in triple-negative breast cancer (TNBC) cells. Our experiments also reveal that this SL interaction can be targeted by small molecule SRC inhibitors, SU6656 and KX2-391, and can be used to improve elimination of human TNBC tumors in a xenograft model. Our observations are of potential practical importance, since TNBC is an aggressive heterogeneous malignancy with a very high rate of patient mortality due to the lack of targeted therapies, and our work indicates that FDA-approved SRC inhibitors may potentially be used in a personalized manner for treating patients with EPHB6-deficient TNBC. Epub 2016 Mar 2. A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies. Turro E(1), Greene D(2), Wijgaerts A(3), Thys C(3), Lentaigne C(4), Bariana TK(5), Westbury SK(6), Kelly AM(7), Selleslag D(8), Stephens JC(9), Papadia S(10), Simeoni I(10), Penkett CJ(10), Ashford S(10), Attwood A(9), Austin S(11), Bakchoul T(12), Collins P(13), Deevi SV(10), Favier R(14), Kostadima M(7), Lambert MP(15), Mathias M(16), Millar CM(4), Peerlinck K(3), Perry DJ(17), Schulman S(18), Whitehorn D(7), Wittevrongel C(3); BRIDGE-BPD Consortium, De Maeyer M(19), Rendon A(20), Gomez K(5), Erber WN(21), Mumford AD(22), Nurden P(23), Stirrups K(10), Bradley JR(24), Raymond FL(25), Laffan MA(4), Van Geet C(3), Richardson S(26), Freson K(27), Ouwehand WH(28). Collaborators: Furie B, Greinacher A, Gresele P, Heemskerk J, Henskens Y, Keeling D, Liesner R, Mangles S, Pasi J, Rondina M, Roughley C, Schulze H, Talks K, Thachil J, Toh CH. Author information: (1)Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. The Src family kinase (SFK) member SRC is a major target in drug development because it is activated in many human cancers, yet deleterious SRC germline mutations have not been reported. We used genome sequencing and Human Phenotype Ontology patient coding to identify a gain-of-function mutation in SRC causing thrombocytopenia, myelofibrosis, bleeding, and bone pathologies in nine cases. Modeling of the E527K substitution predicts loss of SRC's self-inhibitory capacity, which we confirmed with in vitro studies showing increased SRC kinase activity and enhanced Tyr(419) phosphorylation in COS-7 cells overexpressing E527K SRC. The active form of SRC predominates in patients' platelets, resulting in enhanced overall tyrosine phosphorylation. Overactive SRC in patient-derived MKs causes a reduction in proplatelet formation, which can be rescued by SRC kinase inhibition. Stem cells transduced with lentiviral E527K SRC form MKs with a similar defect and enhanced tyrosine phosphorylation levels. FYN expression potentiates FLT3-ITD induced STAT5 signaling in acute myeloid leukemia. Chougule RA(1), Kazi JU(1), Rönnstrand L(1). Author information: (1)Division of Translational Cancer Research, and Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden. FYN is a non-receptor tyrosine kinase belonging to the SRC family of kinases, which are frequently over-expressed in human cancers, and play key roles in cancer biology. SRC has long been recognized as an important oncogene, but little attention has been given to its other family members. We identified multiple FYN binding sites in FLT3, which partially overlapped with SRC binding sites. Notably, SRC depletion in TNBC cell lines phenocopied the effects of miR-34a reintroduction, whereas SRC overexpression rescued the antitumorigenic properties mediated by miR-34a. miR-34a levels also increased when cells were treated with c-SRC inhibitors, suggesting a negative feedback exists between miR-34a and c-SRC. Finally, we found that miR-34a and SRC levels were inversely correlated in human tumor specimens. RESULTS: In the 129 patients, a copy number gain of three chromosome regions-namely, 8q22 (including ESRP1 and CCNE2), 8q24 (including MYC and TNFRSF11B), and 20q11-q13 (including SRC, MMP9, and CSE1L)--conferred poor survival for patients. RESULTS: There were no significant differences in length of follow-up or risk factors for the development of penile cancer between both groups (p = 0.6 and p = 0.5 respectively) Ultimately, the incidence of high risk disease, nodal metasases, high grade disease and pelvic lymph node dissection were significantly greater in patients that were initially managed in a SRC (p = 0.02, p = 0.03, p = 0.004 and p = 0.028 respectively). Patients undergoing initial treatment in a SRC had a non-significantly reduced rate of cancer specific survival (88 Vs 66%, MUH Vs SRCs, p = 0.495) and recurrence free survival (85 Vs 46%, MUH Vs SRCs, p = 0.24). PID 27861374 27835901 27756880 27439479 27438149 27418135 26936507 26848862 26676753 25618371 25444439 LIG1 PID HDAC7 PID MIF Elevated expression of CXCL2 and MIF and an increased number of CD33+ MDSCs were detected in BC tissues, and these increases were significantly associated with advanced disease stage and poor patient prognosis (P<0.01). A positive association was observed between CXCL2 or MIF expression and the number of tumor-infiltrating CD33+ MDSCs (P<0.01). 2016 Apr 20. A Novel MIF Signaling Pathway Drives the Malignant Character of Pancreatic Cancer by Targeting NR3C2. Yang S(1), He P(1), Wang J(1), Schetter A(2), Tang W(2), Funamizu N(3), Yanaga K(3), Uwagawa T(3), Satoskar AR(4), Gaedcke J(5), Bernhardt M(5), Ghadimi BM(5), Gaida MM(6), Bergmann F(6), Werner J(7), Ried T(8), Hanna N(9), Alexander HR(9), Hussain SP(10). Author information: (1)Pancreatic Cancer Unit, National Cancer Institute, Bethesda, Maryland. To identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression, we analyzed the expression of coding and noncoding genes in high and low MIF-expressing tumors in multiple cohorts of pancreatic ductal adenocarcinoma (PDAC) patients. Mechanistically, MIF upregulated miR-301b that targeted NR3C2 and suppressed its expression. PDAC tumors expressing high levels of MIF displayed elevated levels of miR-301b and reduced levels of NR3C2. In addition, reduced levels of NR3C2 expression correlated with poorer survival in multiple independent cohorts of PDAC patients. Furthermore, genetic deletion of MIF disrupted a MIF-mir-301b-NR3C2 signaling axis, reducing metastasis and prolonging survival in a genetically engineered mouse model of PDAC. Addition of MIF increased production of the immune-suppressive enzyme arginase-1 in MDSCs in a CXCR2-dependent manner, whereas blocking MIF reduced arginase-1 production. Similarly to 5-FU, targeting tumor-derived MIF conferred a survival advantage to tumor-bearing animals and increased the cytotoxic T cell response within the tumor. Importantly, tumor cell proliferation, survival, and self-renewal were not impacted by MIF reduction, demonstrating that MIF is primarily an indirect promoter of GBM progression, working to suppress immune rejection by activating and protecting immune suppressive MDSCs within the GBM tumor microenvironment. 2016 Mar. MIF inhibition reverts the gene expression profile of human melanoma cell line-induced MDSCs to normal monocytes. Waigel S(1), Rendon BE(1), Lamont G(1), Richie J(1), Mitchell RA(2), Yaddanapudi K(2). Author information: (1)Molecular Targets Program, JG Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA. (2)Molecular Targets Program, JG Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA; Department of Microbiology and Immunology, University of Louisville, USA; Department of Medicine, University of Louisville, USA. Myeloid-derived suppressor cells (MDSCs) are potently immunosuppressive innate immune cells that accumulate in advanced cancer patients and actively inhibit anti-tumor T lymphocyte responses [1]. Increased numbers of circulating MDSCs directly correlate with melanoma patient morbidity and reduced anti-tumor immune responses [2], [3]. Previous studies have revealed that monocyte-derived macrophage migration inhibitory factor (MIF) is necessary for the immune suppressive function of MDSCs in mouse models of melanoma [4], [5]. To investigate whether MIF participates in human melanoma-induced MDSC differentiation and/or suppressive function, we have established an in vitro MDSC induction model using primary, normal human monocytes co-cultured with human melanoma cell lines in the presence or absence of the MIF antagonist-4-IPP [4], [6], [7], [8], [9]. To identify potential mechanistic effectors, we have performed transcriptome analyses on cultured monocytes and on melanoma-induced MDSCs obtained from either untreated or 4-IPP-treated A375:monocyte co-cultures. Here, we present a detailed protocol, which can facilitate easy reproduction of the microarray results (NCBI GEO accession number GSE73333) published by Yaddanapudi et al. (2015) in Cancer Immunology Research [10]. DOI: 10.1016/j.gdata.2015.12.025 PMCID: PMC4778657 We then generate cross-species expression networks to recapitulate a known association between tumor epithelial cells and fibroblast activation, and propose a potentially novel relationship between two hypoxia-associated genes, human MIF and mouse Ddx6. In this study, we showed that MIF suppressed tumor growth of the TNBC cell lines and patient-derived xenografts in NOD-SCID mice. Furthermore, MIF reduced the TNBC cancer stem cell (CSC) population through down-regulating KLF5 expression, a stem cell transcription factor over-expressed in basal type TNBC and promoting cell proliferation, survival and stemness. Interestingly, MIF suppresses the expression of KLF5 through inducing the expression of miR-153. Taken together, our findings suggest that MIF inhibits basal TNBC via the miR-153/KLF5 axis and MIF may be used for the treatment of TNBC. DOI: 10.7150/thno.14315 PMCID: PMC4775863 Low or negative expression of MIF in both TMAs and of iNOS in the validation set also provided useful prognostic data. First, MIF peptide FLSELTQQL was eluted from the HLA-A2 of the human cancerous ovarian cell lines SKOV3, A2780, OV90, and FHIOSE118hi and detected by mass spectrometry. PID 27721403 27197190 27145382 26981417 26980748 26941846 26783288 26719579 TUBB PID NET1 PID PAK2 PID PAK1 Compared to a cohort of The Cancer Genome Atlas (TCGA) patients with HER2-positive non-IBC, HER2-positive IBC patients had significantly higher mutational and neoantigenic burden, more frequent gain-of-function TP53 mutations and a recurrent 11q13.5 amplification overlapping PAK1. We also found that PAK1 (p21 protein (Cdc42/Rac)-activated kinase 1) signaling was involved in TFAP2C/TGFBR1-induced tumorigenesis. This study shows that TFAP2C promoted tumor progression by upregulation of TGFBR1 and consequent activation of PAK1 signaling. DOI: 10.1038/emm.2016.125 PMCID: PMC5133372 Genomic analysis of P tumors revealed somatic mutations in PIK3CA, KRAS, AKT1, FGFR3, HRAS and BRAF at frequencies of 41%, 6%, 5%, 2%, 1% and 2%, respectively, and CN amplification of CCND1, ZNF703, FGFR1, RSF1 and PAK1 at 23%, 19%, 17%, 12% and 11%, respectively. PID 27923043 27885255 27672107 CLASP1 PID BRCC3 PID RAC3 PID PAK3 PID E2F1 Mechanistically, Tspan5 inhibits the cell cycle transition from G1-S phase by increasing the expression of p27 and p15 and decreasing the expression of cyclin D1, CDK4, pRB and E2F1. The correlation of Tspan5 expression with the expression of p27, p15, cyclin D1, CDK4, pRB and E2F1 in vivo are also revealed in xenografted tumours. Mitochondrial ribosomal protein S18-2 is highly expressed in endometrial cancers along with free E2F1. Mints M(1), Mushtaq M(2), Iurchenko N(3), Kovalevska L(3), Stip MC(2), Budnikova D(3), Andersson S(1), Polischuk L(3), Buchynska L(3), Kashuba E(2)(3). Author information: (1)Department of Women's and Children's Health (KBH), Karolinska Institutet, Stockholm, 17176, Sweden. (2)Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, 17177, Sweden. (3)R.E. Histopathological diagnosis and imaging techniques for EC are limited, thus new prognostic markers are needed to offer patients the best treatment and follow-up.In the present paper we showed that the level of mitochondrial ribosomal protein MRPS18-2 (S18-2) increased in EC compared with the normal endometrium and hyperplasia, based on a study of 42 patient biopsies. Importantly, high expression of free E2F1 in EC correlates well with high S18-2 expression. This may be associated with epithelial-mesenchymal cell transition (EMT).We conclude that high expression of S18-2 and free E2F1, and low pan-keratin, beta-catenin, and E-cadherin signals might be a good set of prognostic markers for EC. DOI: 10.18632/oncotarget.7905 PMCID: PMC5008351 The integration of data from a variety of sources, including gene expression profiles, transcription factor-binding data from ChIP-Seq experiments, curated gene sets, and clinical information of patients, indicated discrete regulatory programs (e.g., controlled by E2F1 and E2F4), with significantly different regulatory activity in one or multiple subtypes of liposarcoma with respect to normal adipose tissue. These programs were also shown to be prognostic, wherein liposarcoma patients with higher E2F4 or E2F1 activity associated with unfavorable prognosis. By contrast, HPV+ HNSCC expresses viral oncogenes E6 and E7, which inhibit TP53 and RB1, and activates the cell cycle regulator E2F1. miR-302b enhances breast cancer cell sensitivity to cisplatin by regulating E2F1 and the cellular DNA damage response. Cataldo A(1)(2), Cheung DG(1), Balsari A(2)(3), Tagliabue E(3), Coppola V(1), Iorio MV(4), Palmieri D(1), Croce CM(1). Author information: (1)Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine and Solid Tumor Biology Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA. (2)Department of Biomedical Sciences for Health, University of Milan, Milan, Italy. (3)Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori of Milan, Milan, Italy. (4)Start Up Unit, Fondazione IRCCS Istituto Nazionale dei Tumori of Milan, Milan, Italy. The identification of the molecular mechanisms involved in the establishment of the resistant phenotype represents a critical need for the development of new strategies to prevent or overcome cancer resistance to anti-neoplastic treatments.Breast cancer is the leading cause of cancer-related deaths in women, and resistance to chemotherapy negatively affects patient outcomes. We also identified E2F1, a master regulator of the G1/S transition, as a direct target gene of miR-302b. E2F1 transcriptionally activates ATM, the main cellular sensor of DNA damage. Through the negative regulation of E2F1, miR-302b indirectly affects ATM expression, abrogating cell-cycle progression upon cisplatin treatment. The TERT promoter SNP rs2853669 decreases E2F1 transcription factor binding and increases mortality and recurrence risks in liver cancer. Ko E(1), Seo HW(1), Jung ES(2), Kim BH(3), Jung G(1). Author information: (1)Department of Biological Sciences, College of Natural Sciences, Seoul National University, Gwanak-gu, Seoul, 151-747, South Korea. (2)Department of Pathology, Seoul St. Epub 2015 Oct 16. Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance. Li B(1), Xu WW(2), Guan XY(3), Qin YR(4), Law S(5), Lee NP(5), Chan KT(6), Tam PY(6), Li YY(2), Chan KW(7), Yuen HF(8), Tsao SW(9), He QY(10), Cheung AL(11). Author information: (1)School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. We found that fluorouracil (5-FU)-resistant esophageal squamous cell carcinoma cell lines, established through exposure to increasing concentrations of 5-FU, showed upregulation of Id1, IGF2, and E2F1. Quantitative real-time PCR, Western blotting, immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays were used to investigate the molecular mechanisms by which Id1 regulates E2F1 and by which E2F1 regulates IGF2. RESULTS: Id1 conferred 5-FU chemoresistance through E2F1-dependent induction of thymidylate synthase expression in esophageal cancer cells and tumor xenografts. Mechanistically, Id1 protects E2F1 protein from degradation and increases its expression by binding competitively to Cdc20, whereas E2F1 mediates Id1-induced upregulation of IGF2 by binding directly to the IGF2 promoter and activating its transcription. The expression level of E2F1 was positively correlated with that of Id1 and IGF2 in human cancers. Sep 8. Epigenetic factor EPC1 is a master regulator of DNA damage response by interacting with E2F1 to silence death and activate metastasis-related gene signatures. Wang Y(1), Alla V(1), Goody D(1), Gupta SK(2), Spitschak A(1), Wolkenhauer O(2), Pützer BM(3), Engelmann D(1). Author information: (1)Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany. (2)Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany. (3)Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany brigitte.puetzer@med.uni-rostock.de. Transcription factor E2F1 is a key regulator of cell proliferation and apoptosis. Recently, it has been shown that aberrant E2F1 expression often detectable in advanced cancers contributes essentially to cancer cell propagation and characterizes the aggressive potential of a tumor. The molecular mechanism by which the pro-apoptotic activity of E2F1 is antagonized is widely unclear. We found that E2F1 directly binds to the EPC1 promoter and EPC1 vice versa physically interacts with bifunctional E2F1 to modulate its transcriptional activity in a target gene-specific manner. Remarkably, nuclear-colocalized EPC1 activates E2F1 to upregulate the expression of anti-apoptotic survival genes such as BCL-2 or Survivin/BIRC5 and inhibits death-inducing targets. The uncovered cooperativity between EPC1 and E2F1 triggers a metastasis-related gene signature in advanced cancers that predicts poor patient survival. Transcript levels of BUB1, E2F1, ESPL1, GTSE1, RAB3B, and U2AF2 were found significantly elevated from normal, ADC, SQC, LCC to SCLC. Tight regulative relationships were found within these genes, while BUB1 and E2F1 were likely to be the drivers. PID 27223087 26959119 26856934 29034103 26623722 26575952 26475334 26350215 26349752 GNAO1 PID TUBB2A PID CDK2 Detection of cell cycle marker expression showed that CDKN3 knockdown promotes cell cycle arrest by decreasing the expression of CDK2, CDC25A, CCNB1, and CCNB2 in human gastric cancer cells. In kinase assays in vitro, LS-007 was more selective for the CDK family, inhibiting CDK2, CDK9, CDK1 and CDK4 at low nanomolar concentrations. A subset of these genes, including CDK2, YAP1, and BIRC5 (Survivin), are members of a common network. We further demonstrated that siRNA knockdown of CDK9, the kinase subunit of positive transcription elongation factor b (P-TEFb), instead of CDK1 or CDK2, reduced the levels of cyclin B1 and MYC in TNBC cell lines. However, we found that cells acquiring resistance to CDK4/6 inhibitors due to CCNE1 amplification could be resensitized by targeting CDK2. Further analysis showed that the S phase promoting factors cyclin-dependent kinase (CDK)1 and CDK2 levels were decreased in RTKN knock-down cells, and that the DNA replication initiation complex proteins Minichromosome maintenance protein complex (MCM)2 and MCM6 were decreased as well in RTKN knock-down cells. Consistent with these findings, a genome-scale pooled RNA interference screen revealed that toxic doses of MK-1775 are suppressed by CDK2 or Cyclin A2 knockdown. PID 27983933 27569395 27337954 27486754 27020857 26935528 26890070 USP21 PID KIF2A PID HDAC9 GEP revealed upregulation of MAPK10, HELIOS, HDAC9, and FYN, as well as downregulation of SH3BP5 and LCK. All MEF2D-BCL9-positive patients had B-cell precursor immunophenotype and were characterized as being older in age, being resistant to chemotherapy, having very early relapse, and having leukemic blasts that mimic morphologically mature B-cell leukemia with markedly high expression of HDAC9. Exogenous expression of MEF2D-BCL9 in a B-cell precursor ALL cell line promoted cell growth, increased HDAC9 expression, and induced resistance to dexamethasone. Hypermethylation for FZD9, MME, BCAP31, HDAC9, PAX6, SCGB3A1, PDGFRA, IGFBP3, and PTGS2 genes most strongly predicted receptor-positive disease. PID 27993968 27507882 26884818 KLC2 PID DYNLL1 PID TUBB1 A support vector machine (SVM) model of paclitaxel response containing genes  ABCB1, ABCB11, ABCC1, ABCC10, BAD, BBC3, BCL2, BCL2L1, BMF, CYP2C8, CYP3A4, MAP2, MAP4, MAPT, NR1I2, SLCO1B3, TUBB1, TUBB4A, and TUBB4B was 78.6% accurate in predicting survival of 84 patients treated with both HT and CT (median survival ≥ 4.4 yr). In addition, a random forest (RF) classifier using a gene signature ( ABCB1, ABCB11, ABCC1, ABCC10, BAD, BBC3, BCL2, BCL2L1, BMF, CYP2C8, CYP3A4, MAP2, MAP4, MAPT, NR1I2,SLCO1B3, TUBB1, TUBB4A, and TUBB4B) predicted >3-year survival with 85.5% accuracy in 420 HT patients. PID 28620450 ATF2 PID METAP2 PID LRIG1 PID PARD3 PID PKN1 PID PKN2 PID PRICKLE1 PID PTPRU PID STK4 PID PAN2 PID ADCY3 PID HIST3H3 PID HK2 The HK2 Dependent "Warburg Effect" and Mitochondrial Oxidative Phosphorylation in Cancer: Targets for Effective Therapy with 3-Bromopyruvate. Lis P(1), Dyląg M(2), Niedźwiecka K(3), Ko YH(4), Pedersen PL(5), Goffeau A(6), Ułaszewski S(7). Author information: (1)Institute of Genetics and Microbiology, University of Wroclaw, Przybyszewskiego Street, 51-148 Wroclaw, Poland. p.lis@dundee.ac.uk. (2)Institute of Genetics and Microbiology, University of Wroclaw, Przybyszewskiego Street, 51-148 Wroclaw, Poland. mariusz.dylag@uwr.edu.pl. (3)Institute of Genetics and Microbiology, University of Wroclaw, Przybyszewskiego Street, 51-148 Wroclaw, Poland. katarzyna.niedzwiecka@uwr.edu.pl. (4)KoDiscovery, LLC, UM BioPark, Suite 502 E&F, 801 West Baltimore Street, Baltimore, MD 21201, USA. kocancer212@yahoo.com. (5)Departments of Biological Chemistry and Oncology and member at large Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2185, USA. ppederse@jhmi.edu. (6)Institut des Sciences de la Vie, Université Catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium. agoffeau@hotmail.com. (7)Institute of Genetics and Microbiology, University of Wroclaw, Przybyszewskiego Street, 51-148 Wroclaw, Poland. stanislaw.ulaszewski@uwr.edu.pl. This review summarizes the current state of knowledge about the metabolism of cancer cells, especially with respect to the "Warburg" and "Crabtree" effects. In addition, hexokinase 2 (HK2) was identified as an indirect target of miR‑155; exogenous overexpression of miR‑155 upregulated the expression of HK2, whereas inhibition of miR‑155 by antisense miRNA suppressed HK2 expression. In addition, HK2‑modulated glucose metabolism was significantly upregulated by overexpression of miR‑155. HK2 was most highly expressed in PDAC metastases, suggesting a link between HK2 and aggressive tumor biology. In support of this we found HK2 expression to be associated with shorter overall survival in PDAC patients undergoing curative surgery. Transient and stable knockdown of HK2 in primary PDAC cell lines decreased lactate production, anchorage independent growth (AIG) and invasion through a reconstituted matrix. Conversely, stable overexpression of HK2 increased lactate production, cell proliferation, AIG and invasion. Stable knockdown of HK2 decreased primary tumor growth in cell line xenografts and decreased incidence of lung metastasis after tail vein injection. Gene expression analysis of tumors with decreased HK2 expression showed alterations in VEGF-A signaling, a pathway important for angiogenesis and metastasis, consistent with a requirement of HK2 in promoting metastasis. Overall our data provides strong evidence for the role of HK2 in promoting PDAC disease progression, suggesting that direct inhibition of HK2 may be a promising approach in the clinic. DOI: 10.18632/oncotarget.9760 PMCID: PMC5593546 PID 27983708 27315591 28915575 PPP2R5E PID PPP2R5A PID PRKCA PID ADAM17 The A Disintegrin and Metalloproteinases ADAM10 and ADAM17 are among the most prominent sheddases, being widely expressed in many tissues, frequently overexpressed in cancer, and promiscuously cleaving diverse substrates. Epub 2016 Aug 19. Metalloproteinases ADAM10 and ADAM17 Mediate Migration and Differentiation in Glioblastoma Sphere-Forming Cells. Siney EJ(1)(2)(3), Holden A(4), Casselden E(4), Bulstrode H(5), Thomas GJ(6), Willaime-Morawek S(4). Author information: (1)Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK. ejs304@soton.ac.uk. (2)Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK. ejs304@soton.ac.uk. (3)Southampton General Hospital, LF51, South Laboratory Block, Southampton, SO16 6YD, UK. ejs304@soton.ac.uk. (4)Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK. (5)Wessex Neurological Centre, University Hospital Southampton, Southampton, SO16 6YD, UK. (6)Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK. Glioblastoma is the most common form of primary malignant brain tumour. We have focused on the role of two closely related metalloproteinases ADAM10 and ADAM17 due to their high expression in glioblastoma and GSCs and their ability to activate cytokines and growth factors. Here, we report that ADAM10 and ADAM17 inhibition selectively increases GSC, but not neural stem cell, migration and that the migrated GSCs exhibit a differentiated phenotype. Our results suggest that therapies against ADAM10 and ADAM17 may promote cancer stem cell migration away from the tumourigenic niche resulting in a differentiated phenotype that is more susceptible to treatment. DOI: 10.1007/s12035-016-0053-6 PMCID: PMC5443867 PID 27895032 27541285 FYN GEP revealed upregulation of MAPK10, HELIOS, HDAC9, and FYN, as well as downregulation of SH3BP5 and LCK. FYN expression potentiates FLT3-ITD induced STAT5 signaling in acute myeloid leukemia. Chougule RA(1), Kazi JU(1), Rönnstrand L(1). Author information: (1)Division of Translational Cancer Research, and Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden. FYN is a non-receptor tyrosine kinase belonging to the SRC family of kinases, which are frequently over-expressed in human cancers, and play key roles in cancer biology. In this report, we have studied the role of FYN in FLT3 signaling in respect to acute myeloid leukemia (AML). We observed that FYN displays a strong association with wild-type FLT3 as well as oncogenic FLT3-ITD and is dependent on the kinase activity of FLT3 and the SH2 domain of FYN. We identified multiple FYN binding sites in FLT3, which partially overlapped with SRC binding sites. To understand the role of FYN in FLT3 signaling, we generated FYN overexpressing cells. We observed that expression of FYN resulted in slightly enhanced phosphorylation of AKT, ERK1/2 and p38 in response to ligand stimulation. Furthermore, FYN expression led to a slight increase in FLT3-ITD-dependent cell proliferation, but potent enhancement of STAT5 phosphorylation as well as colony formation. We also observed that FYN expression is deregulated in AML patient samples and that higher expression of FYN, in combination with FLT3-ITD mutation, resulted in enrichment of the STAT5 signaling pathway and correlated with poor prognosis in AML. Taken together our data suggest that FYN cooperates with oncogenic FLT3-ITD in cellular transformation by selective activation of the STAT5 pathway. Therefore, inhibition of FYN, in combination with FLT3 inhibition, will most likely be beneficial for this group of AML patients. DOI: 10.18632/oncotarget.7128 PMCID: PMC4891096 PID 27993968 26848862 BUB1 Transcript levels of BUB1, E2F1, ESPL1, GTSE1, RAB3B, and U2AF2 were found significantly elevated from normal, ADC, SQC, LCC to SCLC. Tight regulative relationships were found within these genes, while BUB1 and E2F1 were likely to be the drivers. PID 26349752 BUB3 PID CENPA Serial statistical and functional enrichment clustering identified a cluster of 11 overexpressed ARE-mRNAs (CDC6, KIF11, PRC1, NEK2, NCAPG, CENPA, NUF2, KIF18A, CENPE, PBK, TOP2A) that negatively correlated with TTP/HuR mRNA ratios and was involved in the mitotic cell cycle. PID 27197193 CKAP5 PID HGF Partial response was observed in three patients, all of whom were c-Met and HGF high. Heparanase is also taken up by tumor cells where it induced expression of HGF, VEGF and MMP-9 and activated ERK and Akt signaling pathways. Evaluation of serum HGF and CK18 levels in patients with esophageal cancer. Kilic-Baygutalp N(1), Ozturk N(2), Orsal-Ibisoglu E(3), Gündogdu B(4), Ozgeris FB(2), Bakan N(2), Bakan E(2), Kilic AF(5). Author information: (1)Department of Medical Biochemistry, School of Medicine, Ataturk University, Erzurum, Turkey eczbaygutalp80@gmail.com. (2)Department of Medical Biochemistry, School of Medicine, Ataturk University, Erzurum, Turkey. (3)Department of Nuclear Medicine, School of Medicine, Ataturk University, Erzurum, Turkey. (4)Department of Medical Pathology, School of Medicine, Ataturk University, Erzurum, Turkey. (5)Department of Internal Medicine, School of Medicine, Ataturk University, Erzurum, Turkey. Cytokeratins are thought to play a role in apoptosis. In this study, we aimed to compare serum HGF and CK18 levels between esophageal squamous cell carcinoma patients and healthy controls. Venous blood samples were taken; serum HGF and CK18 concentrations were determined via ELISA. Results indicated that serum HGF levels were higher in patients (1.37 ± 0.63 ng/mL) as compared to the healthy subjects (0.41 ± 0.29 ng/mL). In addition, serum HGF and CK18 levels were positively correlated with metastasis stage, tumor stage, and disease stage of esophageal squamous cell carcinoma. To our knowledge, this is the first study to evaluate serum HGF and CK18 levels in patients with esophageal squamous cell carcinoma. The results suggest that serum CK18 and HGF levels may be used as prognostic and disease monitoring biomarkers of esophageal squamous cell carcinoma. DOI: 10.4238/gmr.15038583 Abrogation of matriptase expression by silencing with RNAi or inhibition of matriptase proteolytic activity with a synthetic inhibitor impairs the conversion of inactive pro-HGF to active HGF and subsequent c-Met-mediated signaling, leading to efficient impairment of proliferation and invasion of IBC cells. HGF, the only known ligand for cMET, is found at high levels in both serum and ascites in women with ovarian cancer, and is proposed to induce both migration and metastasis. However, clinically validated biomarkers are not yet available for either HGF or cMET, preventing a clear understanding of the true rate of overexpression, or its correlation with prognosis. Despite this, a number of agents against HGF and cMET are currently being investigated in clinical trials for multiple tumour types, including ovarian. METHODS: Immunohistochemistry (IHC) was used to detect the expression of HGF and MSI in 98 specimens of colorectal cancer. The HGF-expression rate was 71.4%. The patients with an MSI tumor had a significantly higher HGF expression, compared with the patients with an MSS tumor (P=0.048). The multivariate analysis showed that lymphocytic infiltration, TMN stage, MSI and HGF are independent prognostic factors in colorectal cancer (P<0.05 for all). CONCLUSIONS: HGF is highly expressed in colorectal cancer patients with microsatellite instability. Both microsatellite instability and HGF are independent factors affecting the prognosis in patient with colorectal cancer. Importantly, HGF mRNA was significantly up-regulated in pre-OBs versus mature OBs, and CM of pre-OBs activated the MET signaling pathway. Highlighting a key role for HGF, CM from HGF-negative pre-OBs derived from the BMSC line HS27A did not support migration of BC cells. However, we report that rilotumumab does not prevent HGF from directly binding to MET on conventional and primary patient-derived human gliomasphere lines, a trait driven by the HGF α-chain, which remains free to engage cell-surface glycosaminoglycans and the receptor MET. Hence, we confirm that rilotumumab is only a partial antagonist of HGF activity, a finding that has considerable implications for the therapeutic use of rilotumumab. DOI: 10.1080/19420862.2015.1122149 PMCID: PMC4966628 Using cytokine array analysis, we were able to demonstrate that GSC1 cell growth is mediated through hepatocyte growth factor (HGF)/c-MET signaling pathway which is activated exclusively by HGF secreted from GSC-MSC. In patient-derived pancreatic cancer xenografts, nicotine treatment augmented tumor growth and metastasis; tumor lysates from nicotine-treated mice demonstrated elevated HGF expression by qRT-PCR and phospho-Met levels by ELISA. Serum HGF did not significantly differ between patients with PM and healthy controls. Cabozantinib upregulated HIF-1α expression at translational levels and increased the expression of the downstream factors including VEGF, lactate dehydrogenase A (LDHA), HGF, and MET. 2ME2 corrected the activated pathways by cabozantinib through downregulating HIF-1α expression and inhibiting its nuclear translocation in hypoxic MTC cells. PID 27843623 27016342 27706656 27528224 27139908 27087375 26934743 26750997 26676563 26667487 26503729 26219898 C7 PID CSNK2A1 PID CYFIP1 PID ARHGAP9 PID NEDD4 PID PTPN18 PID KLC3 PID PSAP Therefore a combination of positive staining for CK-7, CEA and CA-125; with negative staining for CK-20, PSA and PSAP is the pattern of immunohistochemical findings noted for this rare tumor. PID 27134716 TRAF2 Furthermore, we demonstrate that miR-892b attenuated NF-κB signaling by directly targeting and suppressing multiple mediators of NF-κB, including TRAF2, TAK1, and TAB3, and thus, miR-892b silencing in breast cancer cells sustains NF-κB activity. PID 26747895 RPF1 PID RIPK2 PID CSNK2A2 In the TCGA ovarian cancer dataset, we found 67 genes whose expression levels were negatively correlated with miR-532-5p expression and correlated with patient survival, such as WNT9A, CSNK2A2, CHD4, and SH3PXD2A The potential miR-532-5p-regulated gene targets were found to be enriched in the Wnt pathway. Overexpression of miR-532-5p through miRNA mimic caused downregulation of CSNK2A2, CHD4, and SH3PXD2A in the OVCAR-3 cell line. PID 26873729 AVP MATERIALS AND METHODS: Four patients (3 males, 1 female; median age 69 years) with locally advanced pancreatic body cancer underwent preoperative CHA embolization with AVP. CONCLUSIONS: AVP application is feasible and safe as an embolic procedure for preoperative CHA embolization of DP-CAR. DOI: 10.1007/s00270-016-1509-9 PID 27858118 GNGT2 PID IAPP PID SDC1 The protein biomarker panel (IL8, MMP9, MMP10, ANG, APOE, SDC1, A1AT, PAI1, CA9, VEGFA) was monitored in voided urine samples collected prior to cystoscopy using a custom multiplex ELISA assay. PID 27717367 GNA15 PID GNA14 PID RHOB Here, we show: i) differences in RHOA expression patterns, and its pathway activity, between Asian and Caucasian GC tumors; ii) in vitro and in vivo perturbed RHOA expression inhibits GC cell growth in high RHOA-expressing cell lines; iii) inverse correlation between RHOA and RHOB expression; and iv) an innovative small molecule design strategy for RHOA inhibitors. PID 27806312 AGT PID ADRA2A PID USP16 PID C6 Vertebral fixation with screws on the lateral masses of C3, C5 and C6 and a hook on C1 was performed. METHODS: We examined the circadian clock's impact on the timing of cell death and cell division in curcumin-treated C6 rat glioma cells through continuous video microscopy for several days. Results revealed significant differences among the considered groups in terms of their C6, C8, C10, and C12 fatty acid plasma concentrations. Using rat C6 glioma model, the combined approach successfully monitors the acquisition and decrease of cancer hallmarks. We show that knockdown of the expression of OPN reduces C6 cell proliferation, survival, viability and clonogenicity in vitro, and reduces tumor burden and prolongs animal survival in syngeneic rats. Oncotarget. 2016 May 17;7(20):29216-27. doi: 10.18632/oncotarget.8703. Silencing homeobox C6 inhibits colorectal cancer cell proliferation. Ji M(1), Feng Q(1), He G(1), Yang L(1), Tang W(1), Lao X(1), Zhu D(1), Lin Q(1), Xu P(1), Wei Y(1), Xu J(1). Author information: (1)Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. Homeobox C6 (HOXC6), a member of the homeobox family that encodes highly conserved transcription factors, plays a vital role in various carcinomas. PID 28053744 27680947 27379390 27198662 27081081