Bode, Barrie P.
Ph.D. (Doctor of Philosophy)
Department of Biological Sciences
Liver--Cancer--Treatment; Hepatitis C--Treatment; Biochemical markers
Golgi Protein -- 73kDa (GP73/GOLM1) is a resident cis-Golgi Type II membrane protein that is nearly undetectable in normal hepatocytes, but its expression increases in hepatocytes during hepatocellular carcinoma (HCC) and its serum levels increase in patients with chronic hepatitis C infection and HCC, yet its biological role in the liver and in the pathogenesis of HCC remains unclear. In order to investigate possible biological roles for GP73, hepatocyte-specific GOLM1 null mice (C57BL/6) were created using the Cre-loxP system, with "floxed" GOLM1 gene exon 3 and Cre recombinase driven by the albumin promoter. Mouse genotypes were confirmed by PCR analysis. GOLM1Fl/Fl/Cre(+) animals showed no obvious biological phenotype compared to their Cre(-) littermates. They exhibited normal growth, behaviors, and mated successfully, suggesting that hepatic GP73 is not vital for normal physiological function. Consistent with clinical observations in humans, GP73 expression increased in a chemically induced model of mouse liver fibrosis and carcinogenesis. Examination of GP73 expression in 14 human HCC cell lines revealed that GP73 is consistently expressed in mesenchymal HCC cells (modeling metastatic) but not in most epithelial HCC cell lines. Cell invasion assays indicated that mesenchymal HCC with high GP73 expression were more invasive suggesting a potential role for this protein in metastasis. Silencing in invasive mesenchymal HCC cells suggested that GP73 is necessary for enhanced cell proliferation and over-expression in a non-invasive epithelial HCC cell line suggested that GP73 is sufficient to induce epithelial to mesenchymal transition (EMT) and metastasis. Collectively the results suggest GP73 will serve as a potential therapeutic target for treatment of advanced HCC and that the hepatocyte-specific GP73 knockout mice will serve as a valuable tool to investigate the role of GP73 in HCC development.
Arora, Gunisha, "Hepatocyte specific GP73/GOLM1 knockout mice and human hepatocellular carcinoma cell lines provide insights into the potential roles of GP73 HCC serum biomarker" (2016). Graduate Research Theses & Dissertations. 3363.
ix, 98 pages
Northern Illinois University
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