Effect of Cisd2 Haploinsufficiency on Hepatic Steatosis and Carcinogenesis in Mice

• Main Authors: Zhao-Qing Shen, 沈釗慶
• Other Authors: Ting-Fen Tsai
• Format: Others
• Language: en_US
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/24009056980605363705

碩士 === 國立陽明大學 === 生命科學暨基因體科學研究所 === 99 === Hepatocellular carcinoma (HCC) is a common cancer in the world and a major cause of deaths in Asia and Africa. Understanding the pathogenesis and the molecular mechanism of hepato-carcinogenesis will provide more effective preventive and therapeutic strategies. Previous studies had revealed that frequent allelic loss (~77%) on human chromosome 4q22-25 region occurs in the HCC tissues. These results thus form the basis for positional cloning of the candidate tumor suppressor genes of HCC in this chromosome region. Cisd2, a mitochondrial outer membrane protein, is a candidate of tumor suppressor gene for HCC. Cisd2 is located within the overlapping region of HCC critical region and a human longevity region on chromosome 4q. Preliminary results in our lab revealed that deletion of a single copy of Cisd2 (+/- heterozygous knockout) led to hepatic steatosis and metabolic stress in mice with haplo-insufficiency of the Cisd2 protein. Intriguingly, this phenotype was not observed in the Cisd2 homozygous knockout mice. Accordingly, we hypothesize that Cisd2 is a haplo-insufficient tumor suppressor gene for HCC and there may be a synergistic effect between this metabolic stress and oncogenic factors, such as HBx, during liver carcinogenesis. In this study, we used the mouse genetic approach to investigate the effect of Cisd2 haploinsufficiency on hepatic steatosis and carcinogenesis. We have to used on liver pathogenesis in the Cisd2+/- mice; the liver phenotypes include hepatic steatosis (fatty changes), inflammation and fibrosis. In fact, the pathological features of the mice are similar to those observed in human patients with NAFLD (non-alcoholic fatty liver disease). To study the molecular mechanism underlying this phenotype, we analyzed the expression levels of genes associated with lipid metabolism (lipogenesis and b-oxidation), liver inflammation and fibrosis. Interestingly, our results revealed significant increase of Srebp1c, which is the master regulator of lipogenesis, and its downstream target gene, fatty acid synthase (Fas) in the Cisd2+/- livers. In addition, we have discovered that liver fibrosis was associated with activation of hepatic stellate cells, as revealed by increased expression of a-SMA, in the Cisd2+/- livers. Regarding the promoting effect on carcinogenesis, our preliminary result suggested that Cisd2 haplo-insufficiency can accelerate HCC tumorigenesis in the HBx transgenic mice with Cisd2+/- background; systematic analyze of tumor incidence and latency in these mice is currently ongoing. In summary, our results suggested that Cisd2 is likely to be a haplo-insufficient tumor suppressor for HCC. Heterozygous deficiency of Cisd2 led to abnormal lipid metabolism accompanying with fatty liver, cell death, severe inflammation and fibrosis in the liver. These pathogenic effects may further accelerate HCC development in susceptible mice.