The role of Ovca1 function in liver tumorigenesis

• Main Authors: Hung-Lin Chen, 陳泓霖
• Other Authors: Chun-Ming Chen
• Format: Others
• Language: zh-TW
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/52350573362576394318

碩士 === 國立陽明大學 === 生命科學系暨基因體科學研究所 === 104 === Ovca1 is a tumor suppressor gene and is involved in the diphthamide biosynthesis pathway. Diphthamide is a post-translational modification of His715 on eukaryotic Elongation Factor 2 (eEF2) to maintain the fidelity of elongation process during mRNA translation. In previous studies, Ovca1 heterozygous mutant mice are tumor-prone. However, the role of Ovca1 in liver tumorigenesis remains unclear. Thus, we generated Ovca1 liver-specific knockout mice, Alb-Ovca1fx/fx, in this study. Interestingly, serum levels of alanine aminotransferase (ALT), triglyceride (TG) and total cholesterol (TCHO) were higher in Alb-Ovca1fx/fx mice than those in control mice. We also observed liver inflammation and fibrosis in part of mutant mice. Furthermore, TUNEL assay revealed that apoptotic events in liver were increased in Alb-Ovca1fx/fx mice. However, we found no liver tumor formation in Alb-Ovca1fx/fx mice at 15 months of age. Upon administration of the hepatic carcinogen, diethylnitrosamine (DEN), we observed higher ALT levels in Alb-Ovca1fx/fx mice 24 hours after DEN treatment, suggesting that Alb-Ovca1fx/fx mice were more sensitive to DEN-induced liver damage. However, there was no significant difference between control and mutant mice in the compensatory proliferation using immunohistochemistry staining with antibodies against Ki67 and BrdU. On the other side, Pten plays an important role in liver cancer. Pten liver-specific knockout mice will promote tumor growth. Thus, we generated Ovca1 and Pten liver-specific knockout mice, Alb-Ovca1fx/fx；Ptenfx/fx . We found tumor formation in Alb-Ovca1fx/fx；Ptenfx/fx mice at 6 months of age. Furthermore, serum levels of ALT, TG and TCHO were higher in Alb-Ovca1fx/fx；Pten fx/fx mice than Alb-Pten fx/fx mice. Taken together, our findings suggest that the loss of Ovca1 in the liver leads to the promotion of liver tumorigenesis in DEN-treated and Pten null conditions.