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FUNCTIONAL ANALYSIS OF PROTO-ONCOGENE c-KIT IN THE DEVELOPMENT AND PROGRESSION OF HEPATOCELLULAR CARCINOMA

Zhang, Qiangnu

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Abstract

Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy and second leading cause of cancer-related deaths worldwide. Despite recent advances in diagnosis and molecular understanding, limited success was obtained in improving the survival of HCC patients. Molecular targeted therapies provide an opportunity to expand life expectancy of patients. However, up to now only sorafenib, a multikinase inhibitor, showed survival benefits in some patients. Thus, there is an urgent demand to discover novel molecular targets in HCC to improve therapeutic outcome. As a receptor tyrosine kinase, c-KIT participates in intracellular signaling. Aberrant expression or mutation of c-KIT plays an oncogenic role and inhibition of c-KIT has shown promising results in some cancer. However, the role of c-KIT in HCC is still unclear and the potential of utilizing c-KIT as a therapeutic target in HCC needs to be assessed. Thus, the main aim of this thesis was to analyze the functional role of c-KIT and illuminate its relevant mechanism in the progression of HCC. Using public datasets of patients with HCC, the clinical relevance of c-KIT was analyzed. In vitro, activation of downstream pathways which are regulated by c-KIT was investigated. Moreover, functional analysis was performed using c-KIT overexpression and knock-down in HCC cell lines. Meanwhile, two patient derived mutations of c-KIT (W262C and C674F) were considered in the process of analysis. Based on RNA microarray data from patients and RNA sequencing data from HCC cells, candidate genes that are regulated by c-KIT were selected and validated using bioinformatics methods and in vitro experiments. The results showed that high c-KIT indicated poor outcome of patients. c-KIT activation regulated PI3K/AKT and MAPK pathways in HCC cells. No effect of c-KIT on proliferation was observed, but the migration of HCC cell lines was promoted by c-KIT possibly by induction of epithelial-mesenchymal transition. The c-KIT mutation W262C led to loss of functional c-KIT signaling. The analysis of large HCC gene expression data sets revealed the genes PLXDC1, KCNJ2, JAM3, and GJA1 which may be regulated by c-KIT. Interestingly, PLXDC1, KCNJ2 and GJA1 expression correlated with prognosis of HCC patients and their function is very likely involved in cell migration. Taken together, the data presented here support that c-KIT plays an oncogenic role in HCC and targeting c-KIT may benefit patient outcome.

Item Type: Dissertation
Supervisor: Rössler, Dr. Stephanie
Date of thesis defense: 9 July 2019
Date Deposited: 23 Aug 2019 05:51
Date: 2019
Faculties / Institutes: Medizinische Fakultät Heidelberg > Pathologisches Institut
Subjects: 610 Medical sciences Medicine
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