Abstract 1323: Liver-specific knockout mice and liver-derived cell lines provide insights into potential roles for the GP73/GOLM1 HCC serum biomarker - association with sustained cell proliferation

Abstract

Abstract Golgi Protein-73kDa (GP73/GOLM1) is a resident cis Golgi Type II membrane protein that is nearly undetectable in normal liver, but whose expression is upregulated in hepatocellular carcinoma (HCC) and whose circulating levels increase in the plasma of patients with chronic liver disease and HCC. As such, it is the subject of ongoing clinical trials investigating its use as a serum biomarker for HCC. GP73/GOLM1 is cleaved by a proprotein convertase and secreted by proliferating cells, an activity possibly elevated in cancer, yet its biological role in the liver and in the pathogenesis of HCC remains unclear. In order to investigate possible biological roles for GP73/GOLM1, liver-specific knockout mice (C57BL/6) were generated using the Cre-loxP system, characterized by a “floxed” GOLM1 gene and Cre recombinase driven by the albumin promoter. GP73/GOLM1 Cre+/−genotypes were confirmed by PCR analysis. GP73/GOLM1Fl/Fl/Cre(+) animals showed no obvious biological phenotype compared to their Cre(-) littermates, and exhibited normal growth, behavior, and successful mating, suggesting that hepatic GP73/GOLM1 is not vital for normal physiological function, as might be hypothesized from its normally low expression in the liver. Previous studies indicated that GP73/GOLM1 expression was not upregulated in post-hepatectomy liver regeneration, suggesting that its activated expression in the liver is linked to inflammatory or carcinogenic processes rather than transiently increased mitosis. Examination of GP73/GOLM1 expression in 14 human HCC cell lines revealed similar expression levels in epithelial and mesenchymal cell lines, and in an SV40-transformed nontumorigenic human liver epithelial cell line. Rodent in vitro models of hepatocellular transformation revealed equal GP73/GOLM1 expression levels in nontumorigenic parent cell lines and their transformed tumorigenic derivatives. Collectively, the data from the in vivo and in vitro models thus far do not support a direct association of GP73/GOLM1 expression with liver mitogenesis or differentiation, but rather suggest that its expression may be linked to a sustained commitment to cell proliferation - such as occurs in cell lines, liver disease and cancerous transformation, promoted by an inflammatory microenvironment. Possible mechanistic roles for GP73/GOLM1 in HCC development and progression are currently being tested in carcinogenesis models with liver-specific knockout mice. A website on GP73/GOLM1 has also been established as a resource for the research community interested in the study of this protein. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1323. doi:1538-7445.AM2012-1323