| Summary: | 碩士 === 國立陽明大學 === 臨床醫學研究所 === 101 === Primary liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Hepatocellular carcinoma (HCC) accounts for more than 80% of primary liver cancers. The expression of Glycine N-methyltransferase (GNMT), a tumor suppressor gene for HCC, is down-regulated in more than 75% HCC patients. Previously, we reported that very high rate of Gnmt gene knockout mice developed HCC at about fourteen to eighteen months. The objective of this study is to establish and characterize HCC cell line from this mouse model. We established three liver cancer cell lines, Ymac-1, Ymac-2, and Ymac-4. To investigate the tumorigenicity of these cell lines in vivo, they were injected subcutaneously into NOD/SCID mice. Ymac-1 and Ymac-4 can form tumor in vivo, but Ymac-2 cannot. The histopathological study of tumors from Ymac-1 and Ymac-4 revealed that Ymac-1 has spindle shape like sarcomatoid hepatocyte carcinoma (SHC) morphology and Ymac-4 has bile duct like Cholangiocarcinoma morphology. In clinical, SHC is a very rare histologic variant of primary HCC with an incidence of 1.8% in surgically resected cases. The survival rate and prognosis in the SHC group was significantly poor than that in the ordinary HCC group. Moreover, SHC has high metastatic potential. A sarcomatous appearance was found in 20.9% of the cases undergoing TAE/TACE and in 4.2% of the cases not undergoing TAE/TACE. Thus we further characterized Ymac-1 cells. Ymac-1 cells showed a higher resistance to chemotherapy drug, for example, 5-fluorouracil. Results from qPCR analysis showed that EMT marker, like Slug, ZEB1, and N-cadherin were highly expressed in Ymac-1 cells. In addition, we have demonstrated that as few as 500 Ymac-1 cells can form tumor in NOD/SCID mice. Moreover, Ymac-1 has sphere formation ability. Elevated levels of stemness markers, like Sox2, Oct4, CD90, Nanog, GRP78 and CD13 were also observed in these sphere. Taken together, Ymac-1 cells are a very good model for SHC research. It will also be useful for identification of novel biomarkers for HCC recurrence and drug screening.
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