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Title: Mechanism of C/EBP Alpha and C/EBP Beta in pathogenesis of hepatocellular carcinoma
Author: Zhao, Xiaoyang
ISNI:       0000 0004 7427 7061
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Hepatocellular carcinoma (HCC) is generally accompanied by high morbidity and mortality as well as a low cure rate. Decades of investigations have provided insight into the molecular pathogenesis of HCC, where the majority of studies have been focused on transcription factors and their influence in aberrant cell growth. C/EBP Alpha is a member of the large CCAAT/enhancer-binding protein (C/EBP) family of bZIP transcription factors. C/EBP Alpha is a liver enriched transcription factor that regulates the expression of genes involved in hepatic glycogen synthesis, lipid homeostasis, and gluconeogenesis, as well as negatively modulating hepatocyte proliferation. It has previously been proved that enhancing C/EBP Alpha expression by short-activating RNAs (saRNA) can decrease tumour burden and improve liver function in cirrhotic rats with spontaneous HCC. New evidence is now emerging that C/EBP Alpha and C/EBP Beta may play a crucial role in regulating cell proliferation and hepatocyte function. Much is to be learnt about these transcription factors and their role as a potential tool for liver regeneration. The aim of this project is to further elucidate the mechanism of C/EBP Alpha and C/EBP Beta in the pathogenesis of hepatocellular carcinoma and investigate the molecular mechanistic character of saRNA induced RNA activation (RNAa). By doing so, we aim to understand how this protein encoded by an intronless gene can homodimerise and heterodimerise at the promoters and enhancers of a wide range of genes to regulate and maintain normal hepatocyte function. We found that C/EBP Alpha activation promotes anti-proliferative effect in differentiated HCC, and the addition of siRNA to another C/EBP family member-C/EBP Beta converts undifferentiated cell line into sensitive as it abrogates the dominant oncogenic effect of 30kDa isform of C/EBP Beta. Functional synergy of C/EBP Alpha and C/EBP Beta promotes anti-proliferative effect in both differentiated and undifferentiated HCC. For the mechanism of saRNA induced RNA activation, we confirmed that saRNA induced RNA activation works via interacting with hnRNPA2/B1 and DDXn in differentiated HCC by investigating the direct binding partners within saRNA protein complex which are involved in saRNA function. On this basis, we may reconstruct the journey of converting undifferentiated HCC to a more sensitive phenotype by upregulating the expression of these functional saRNA binding partners.
Supervisor: Habib, Nagy Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral