SYSTEMS BIOLOGY ANALYSIS OF KINASE INHIBITORS IN LIVER CANCER CELLS USING NEXT GENERATION SEQUENCING DATA

2021-9-06
Narcı, Kübra
The underlying mechanism for the development of Hepatocellular Carcinoma (HCC) is highly complex due to tissue heterogeneity. Although the traditional approaches mainly focus on a single gene or locus, understanding the variations in the signaling pathways of cancerogenic cells during hepatocarcinogenesis may help to develop novel strategies for treatment and drug development to prevent cancer progression in the patients. This thesis study primarily focuses on unveiling the transcriptome sequencing of differentially expressed genes in HCC, which mainly concentrate on known disease signaling pathways. For this purpose, RNA-seq data of two HCC cell lines were targeted by three different kinase inhibitors and two of their combinations with Sorafenib. The functional pathways enriched with differentially expressed genes were identified by solving a graph problem called as Prize Collecting Steiner Tree (PCST) on human interactome generating inhibitor specific networks. As a result of this study, we found that combinatory treatment of Sorafenib with PIK-75 to HCC cell lines Huh7 and Mahlavu stimulates apoptosis, while TGX-221 with Sorafenib strikingly promotes cell growth antagonizing cellular death, especially for Mahlavu cell line. The states of transcriptomes for different kinase inhibitors were visualized using Cytoscape and molecular interactions were scanned deeply to understand synergistic or antagonistic effects of these kinase inhibitory treatments. Hence, this study provides comprehensive pathways analysis for differential kinase inhibitor reactions of HCC. Using these data, novel HCC drug targets were identified which may lead to more cost-effective and diverse treatment options available for the treatment of liver cancer.

Suggestions

Systems-level analysis reveals multiple modulators of epithelial-mesenchymal transition and identifies DNAJB4 and CD81 as novel metastasis inducers in breast cancer
Kagiali, Zeynep Cansu Üretmen; Sanal, Erdem; Karayel, Özge; Polat, Ayşe Nur; Saatçi, Özge; Ersan, Pelin Gülizar; Trappe, Kathrin; Renard, Bernhard Y.; Önder, Tamer T.; Tunçbağ, Nurcan; Şahin, Özgür; Özlü, Nurhan (American Society for Biochemistry & Molecular Biology (ASBMB), 2019-09)
Epithelial-mesenchymal transition (EMT) is driven by complex signaling events that induce dramatic biochemical and morphological changes whereby epithelial cells are converted into cancer cells. However, the underlying molecular mechanisms remain elusive. Here, we used mass spectrometry based quantitative proteomics approach to systematically analyze the post-translational biochemical changes that drive differentiation of human mammary epithelial (HMLE) cells into mesenchymal. We identified 314 proteins out...
DETECTION OF CIRCULAR RNAS IN HEPATOCELLULAR CARCINOMA TREATED WITH DIFFERENT THERAPEUTIC AGENTS USING RNA-SEQ DATA
Tamkoç, Burcu; Acar, Aybar Can; Özen, Can; Department of Biotechnology (2021-9-8)
Discovering therapeutic agents for hepatocellular carcinoma (HCC) pose challenges as HCC contains high heterogeneity in terms of molecular phenotypes. It is thus crucial to understand the role of circular RNAs in the treatment of HCC. Circular RNAs are small and non-coding endogenous RNAs that have single stranded and covalently bound structures. The clinical importance of circular RNAs is due to their high stability in the serum and tissue. Up to now, the detection of circular RNAs was done through specifi...
Targeting PI3K/Akt/mTOR Pathway Identifies Differential Expression and Functional Role of IL8 in Liver Cancer Stem Cell Enrichment
Kahraman, Deniz Cansen; Atalay, Rengül (2019-11-01)
Activation of the PI3K/Akt/mTOR pathway is an important signaling mechanism involved in the development and the progression of liver cancer stem cell (LCSC) population during acquired Sorafenib resistance in advanced hepatocellular carcinoma (HCC). Therefore, identification of novel therapeutic targets involving this pathway and acting on LCSCs is highly essential. Here, we analyzed the bioactivities and the molecular pathways involved in the action of small-molecule PI3K/Akt/mTOR pathway inhibitors in comp...
Examination of the dielectrophoretic spectra of MCF7 breast cancer cells and leukocytes
Çağlayan, Zeynep; Demircan Yalçın, Yağmur; Külah, Haluk (Wiley, 2020-03-01)
The detection of circulating tumor cells (CTCs) in blood is crucial to assess metastatic progression and to guide therapy. Dielectrophoresis (DEP) is a powerful cell surface marker-free method that allows intrinsic dielectric properties of suspended cells to be exploited for CTC enrichment/isolation from blood. Design of a successful DEP-based CTC enrichment/isolation system requires that the DEP response of the targeted particles should accurately be known. This paper presents a DEP spectrum method to inve...
Evaluation of methylation profiles of an epidermal growth factor receptor gene in a head and neck squamous cell carcinoma patient group
Mutlu, M.; Mutlu, Pelin; Azarkan, S.; Baylr, Ö.; Öcal, B.; Saylam, G.; KORKMAZ, MEHMET HAKAN (2021-03-23)
Upregulation of the epidermal growth factor receptor (EGFR) gene has shown an important impact on the development of head and neck cancers due to its important regulation role on multiple cell signaling pathways. The aim of this study was to investigate the methylation pattern of the promoter region of the EGFR gene between head and neck squamous cell carcinoma (HNSCC) patients and a control group. Forty-seven unrelated HNSCC patients, clinically diagnosed at the Department of Otorhinolaryngology, Dlşkapl Y...
Citation Formats
K. Narcı, “SYSTEMS BIOLOGY ANALYSIS OF KINASE INHIBITORS IN LIVER CANCER CELLS USING NEXT GENERATION SEQUENCING DATA,” Ph.D. - Doctoral Program, Middle East Technical University, 2021.