Abstract
Non-alcoholic steatohepatitis (NASH) has become a major risk factor for hepatocellular cancer (HCC) due to the worldwide increasing prevalence of obesity. However, the pathophysiology of NASH and its progression to HCC is incompletely understood. Thus, the aim of this study was to generate a model specific NASH-derived HCC cell line. A murine NASH-HCC model was conducted and the obtained cancer cells (N-HCC25) were investigated towards chromosomal aberrations, the expression of cell type-specific markers, dependency on nutrients, and functional importance of mTOR. N-HCC25 exhibited several chromosomal aberrations as compared to healthy hepatocytes. Hepatocytic (HNF4), EMT (Twist, Snail), and cancer stem cell markers (CD44, EpCAM, CK19, Sox9) were simultaneously expressed in these cells. Proliferation highly depended on the supply of glucose and FBS, but not glutamine. Treatment with a second generation mTOR inhibitor (KU-0063794) resulted in a strong decrease of cell growth in a dose-dependent manner. In contrast, a first generation mTOR inhibitor (Everolimus) only slightly reduced cell proliferation. Cell cycle analyses revealed that the observed growth reduction was most likely due to G1/G0 cell cycle arrest. These results indicate that N-HCC25 is a highly proliferative HCC cell line from a NASH background, which might serve as a suitable in vitro model for future investigations of NASH-derived HCC.
Highlights
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide [1]
The high recurrence rate of HCC is especially based on the survival of cancer stem cells (CSCs), which are a subpopulation of cells that are resistant to chemotherapy and radiation [9]
Initial fibrosis mostly develops within portal tracts, which leads to persistent portal inflammation, cirrhosis, and HCC
Summary
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide [1]. Despite a significant anti-proliferative effect in preclinical studies [36,37] and success in the therapy of other solid tumors [38], no survival benefit was shown for single agent first generation inhibitor treatment of HCC in clinical studies [39] These rapalogs are being investigated in combination with other drugs in patients with advanced HCC [38]. While Everolimus currently serves as an additive in clinical studies for advanced HCC and as adjuvant therapy in HCC patients after liver transplantation or TACE to prevent HCC recurrence [38], the growth inhibiting effects of the highly specific mTORC1/mTORC2 inhibitor KU-0063794 [45] were shown for HepG2 both in vitro and in vivo [46].
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