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Cataloged from PDF version of article. Thesis (M.S.): Bilkent University, Department of Molecular Biology and Genetics, İhsan Doğramacı Bilkent University, 2020. Includes bibliographical references (leaves 53-61). Hepatocellular carcinoma (HCC) is the second leading cause of cancer related deaths worldwide. The reasons behind high mortality in HCC patients include late diagnosis and lack of therapeutic option. Sorafenib is the only FDA approved systemic therapy for advanced HCC patients but it improves patients’ survival with only 4 months. For this reason, better understanding of the mechanisms of tumor initiation, development and drug resistance in HCC would create new treatment opportunities for HCC patients. In this study, the role of IKKε in HCC tumorigenesis is analysed. HCC development is tightly related to inflammation and IKKε is an inflammation related kinase with very well-known roles in regulating NF-κb and interferon signalling upon viral infection. However, it has also been linked to tumorigenesis of multiple cancers including breast cancer, pancreatic cancer and ovarian cancer. Loss of function models via shRNA or CRISPR/Cas9 are used to study the role of IKKε in HCC tumorigenesis. Depletion of IKKε in HepG2 cells improves the proliferation and anchorageindependent growth of the cells in vitro and it induces a decrease in the expression of EMT markers. Similarly, IKKε depleted HepG2 cells withstand higher doses of Sorafenib, hence, supporting a tumor suppressive potential of IKKε in tumor initiation stages. However, IKKε appears to be involved in EMT and upregulated in EGF and TGFβ1 signalling, two important signalling inducing EMT in HepG2 cells. IKKε is also shown to be upregulated in Sorafenib resistant HepG2 cells where its pharmacological inhibition sensitized Sorafenib resistant HepG2 cells to Sorafenib. These finding show an oncogenic potential of IKKε in later stages of tumor development including metastasis and drug resistance. The results presented in this study suggests a dual role of IKKε in HCC development and drug resistance. Therefore, further mechanistic analysis on this involvement could reveal IKKe inhibition as a potential therapeutic strategy for overcoming Sorafenib resistance in HCC patients. by Erta Xhafa M.S. |
