Liver cancer is the 7th most common and 3rd most lethal malignancy in humans worldwide, and it is one of the few types of cancers that still have a rising incidence rate and death rate in the United States. Hepatocellular carcinoma (HCC) accounts for about 90% of liver cancer cases. The incidence rate and death rate of HCC are increasing faster in females than in males, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) is the rising etiology for HCC in both sexes. The molecular mechanisms of HCC development are poorly understood, and the current theories have contributed very little to the medical practices for HCC. Nuclear receptor coactivator 5 (NCOA5) and 30-kDa Tat-interacting protein (TIP30, also known as HTATIP2) are two transcriptional coregulators involved in HCC development. My dissertation research uses novel genetically engineered mice with manipulated NCOA5 and TIP30 expression to model spontaneous HCC development and fill in the knowledge gaps in the molecular mechanisms of NAFLD/NASH-related HCC development in both sexes. The first part of my research identified p21Cip1/Waf1 (also known as cyclin-dependent kinase inhibitor 1A, CDKN1A) as the critical factor upregulated in hepatocytes by Ncoa5 deficiency in male mice and promotes a pro-tumorigenic inflammatory microenvironment that results in spontaneous HCC. The second part of my research discovered that NCOA5 haploinsufficiency in myeloid-lineage cells sufficiently causes NASH and HCC in male mice. I identified platelet factor 4 (PF4) overexpression in the intrahepatic macrophages of male mice with myeloid-lineage-specific Ncoa5 deletion as a potent mediator to trigger lipid accumulation in hepatocytes by inducing lipogenesis-promoting gene expression. The third part of my research discovered that heterozygous Tip30 deletion promotes HCC development in Ncoa5+/- mice in a female-biased manner. The mechanisms of HCC development in female mice appear different from those in males. I identified hyperpolarization-activated cyclic nucleotide-gated cation channel 3 (HCN3) as a novel oncogenic factor for female HCC that is upregulated by Ncoa5 and Tip30 deletion specifically in female mice. In summary, my dissertation study established p21 and PF4 as novel factors that promote a pro-tumorigenic microenvironment in the development of NASH-related HCC and identified HCN3 as a novel female-biased HCC driver. My work highlights the crucial role of the pro-tumorigenic microenvironment in HCC development and exposes that mechanisms of HCC development can differ significantly in males and females.
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