Browsing by Subject "Gefitinib"
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Item Open Access Identifying TBK1-specific roles in colorectal cancer(Bilkent University, 2022-06) Bagheralmoosavi, ServinColorectal cancer (CRC) is the second most lethal cancer type, with a high incidence rate among adults. The CRC is a highly heterogenic disease with a high rate of mutations in different molecular pathways. Moreover, resistance to standard treatment options is seen frequently among CRC patients. Therefore, a better understanding of the mechanisms behind the initiation, progression, and drug resistance allows us to increase the life quality of CRC patients. TBK1 is a kinase protein with central roles in most cellular signaling pathways. This protein has been reported to be an oncogene in some cancer types. However, the role of TBK1 in colorectal cancer is not yet established. In this study, we generated stable TBK1 knockdown CRC cell lines and mainly focused on the role of TBK1 in colorectal cancer pathogenesis. Upon TBK1 depletion in CRC, we observed increased cell proliferation and migration in vitro. The role of TBK1 in cell proliferation is further confirmed in xenograft models in vivo. Moreover, a shift in EMT and resistance to Gefitinib, an EGFR inhibitor, is indicated in TBK1 knockdown cells. TBK1 is also diminished in our Gefitinib-resistant CRC cell lines, suggesting a role for this protein in drug resistance. The findings of this study suggest a tumor-suppressive role for TBK1 in CRC. Hence, further investigations on the mechanisms behind this tumor-suppressive role of TBK1 in CRC will pave the way for developing novel therapeutic options for CRC treatment.Item Open Access Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal(American Association for the Advancement of Science (A A A S), 2013) Gao J.; Aksoy, B. A.; Dogrusoz, U.; Dresdner, G.; Gross, B.; Sumer, S. O.; Sun, Y.; Jacobsen, A.; Sinha, R.; Larsson, E.; Cerami, E.; Sander, C.; Schultz, N.The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics. © 2013 American Association for the Advancement of Science.Item Open Access The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelialmesenchymal transition in breast cancer(Impact Journals LLC, 2016) Raza, U.; Saatci, O.; Uhlmann, S.; Ansari, S. A.; Eyüpoglu, E.; Yurdusev, E.; Mutlu, M.; Ersan, P. G.; Altundağ, M. K.; Zhang, J. D.; Dogan, H. T.; Güler, G.; Şahin, Ö.Tumor cells develop drug resistance which leads to recurrence and distant metastasis. MicroRNAs are key regulators of tumor pathogenesis; however, little is known whether they can sensitize cells and block metastasis simultaneously. Here, we report miR-644a as a novel inhibitor of both cell survival and EMT whereby acting as pleiotropic therapy-sensitizer in breast cancer. We showed that both miR-644a expression and its gene signature are associated with tumor progression and distant metastasis-free survival. Mechanistically, miR-644a directly targets the transcriptional co-repressor C-Terminal Binding Protein 1 (CTBP1) whose knock-outs by the CRISPRCas9 system inhibit tumor growth, metastasis, and drug resistance, mimicking the phenotypes induced by miR-644a. Furthermore, downregulation of CTBP1 by miR-644a upregulates wild type- or mutant-p53 which acts as a 'molecular switch' between G1-arrest and apoptosis by inducing cyclin-dependent kinase inhibitor 1 (p21, CDKN1A, CIP1) or pro-apoptotic phorbol-12-myristate-13-acetate-induced protein 1 (Noxa, PMAIP1), respectively. Interestingly, an increase in mutant-p53 by either overexpression of miR-644a or downregulation of CTBP1 was enough to shift this balance in favor of apoptosis through upregulation of Noxa. Notably, p53- mutant patients, but not p53-wild type ones, with high CTBP1 have a shorter survival suggesting that CTBP1 could be a potential prognostic factor for breast cancer patients with p53 mutations. Overall, re-activation of the miR-644a/CTBP1/p53 axis may represent a new strategy for overcoming both therapy resistance and metastasis.