IDENTIFICATION OF CELLULAR STRESS RELATED BIOMOLECULES FOR EVENTUAL USE IN TARGETED THERAPIES OF HEPATOCELLULAR CARCINOMA

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2021-9-06

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Gözen, Damla

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Hepatocellular carcinoma (HCC) is one of the most common and deadly cancer types. HCC cells generally display increased resistance to various stress conditions such as oxidative stress. There are conventional therapies used in treatment of HCC but their efficacies are low due to resistance gained by cancer cells and off-target effects. In this thesis study, the aim is to analyze oxidative stress-related gene expression profiles of HCC cell lines to determine genes that could be targeted in novel diagnostic and therapeutic strategies. Selenium (Se) deficiency dependent model of oxidative stress was utilized to identify the genes that are involved in resistance to oxidative stress. The results of a transcriptome-wide gene expression data were analyzed in which differentially expressed genes (DEGs) were identified between HCC cells that are either resistant or sensitive to Se-deficiency dependent oxidative stress. They were further investigated for their importance by cell signaling network analysis. 27 genes were defined to have key roles; 16 of which were previously shown to have impact on patient survival with primary liver cancer. Moreover, the expression of the majority of these genes were found to be correlated with p53-MDM2 pathway. Hence cytotoxic effects of novel small molecules targeting p53-MDM2 protein-protein interaction were tested on 4 HCC cells. Two compounds were shown to induce apoptosis in HCC cells and led to nuclear localization of p53. Altogether, genes identified in this study are proposed to be novel targets for diagnostic and therapeutic approaches and the p53-MDM2 inhibitors have potentials in HCC treatment.

Subject Keywords

Hepatocellular carcinoma, Oxidative stress, Selenium, Hepatitis B virus, Transcriptome-wide analysis

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https://hdl.handle.net/11511/93104

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Graduate School of Informatics, Thesis

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Citation Formats

D. Gözen, “IDENTIFICATION OF CELLULAR STRESS RELATED BIOMOLECULES FOR EVENTUAL USE IN TARGETED THERAPIES OF HEPATOCELLULAR CARCINOMA,” Ph.D. - Doctoral Program, Middle East Technical University, 2021.