Abstract 2145: Overexpression of c-Myc facilitates hepatocarcinogenesis with altering lipid metabolism in tumors induced by activated Akt and mutant Hras
Authors: Xin Bing , Yamamoto Masahiro , Chen Xi , Fujii Kiyonaga , Ooshio Takako , Nishikawa Yuji 
Published: August 2015

Activation of c-Myc plays an important role in many biological processes, including cell growth, proliferation, apoptosis and energy metabolism. Overexpression of c-Myc has been observed in human hepatocellular carcinoma, with an inverse correlation between its expression levels and prognosis of the patients. It has been reported in a mouse model that liver-specific overexpression of c-Myc induces hepatocellular carcinoma, while its subsequent inactivation leads to tumor regression, suggesting that c-Myc expression might be important in hepatocarcinogenesis, as well as maintenance of the liver tumors. In this study, we explored the role of c-Myc in mouse liver tumor models using the Sleeping Beauty transposon-mediated gene integration. The activated Akt (myrAkt), mutant Hras (HrasV12), and c-Myc genes were introduced in various combinations into mouse hepatocytes in vivo through hydrodynamic tail vein injection. When myrAkt and HrasV12 were injected simultaneously, multiple tumors developed after 6 to 8 weeks. During the rapid hepatocarcinogeneis, preneoplastic cells with abundant cytoplasmic lipid transformed into less fatty and more proliferative tumor cells. c-Myc immunohistochemistry revealed that fatty preneplastic hepatocytes were negative, while some of the highly proliferative tumor cells were positive, indicating that secondary activation of c-Myc and altered lipid metabolism might be involved in the neoplastic transformation in this model. We then investigated the effects of introduction of c-Myc into hepatocytes. Although the injection of c-Myc alone was insufficient to induce tumor formation, the combination of c-Myc and myrAkt induced multinodular tumors within 8 weeks. In the early preneoplastic lesions (4 weeks), cells contained various amounts of cytoplasmic lipid, with a tendency that less fatty cells were more proliferative. Fully developed tumors after 8 weeks were composed of thick trabecular arrangements of highly proliferative hepatocyte-like tumor cells with plump nuclei containing prominent nucleoli, characteristically devoid of cytoplasmic lipid, compatible with moderately hepatocellular carcinoma. When c-Myc was introduced with myrAkt and HrasV12, multiple liver tumors developed quite rapidly as early as 2 weeks. The tumors showed the histology of poorly differentiated HCC without lipid accumulation. The cells in the earliest preneoplastic lesions found after 1 week contained only a small amount of cytoplasmic lipid. In conclusion, our results demonstrate that c-Myc facilitates hepatocarcinogenesis and suggest that there might be a link between altered lipid metabolism and proliferation of hepatocytic tumor cells.

Citation Format: Bing Xin, Masahiro Yamamoto, Xi Chen, Kiyonaga Fujii, Takako Ooshio, Yuji Nishikawa. Overexpression of c-Myc facilitates hepatocarcinogenesis with altering lipid metabolism in tumors induced by activated Akt and mutant Hras. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2145. doi:10.1158/1538-7445.AM2015-2145