| Summary: | 碩士 === 國立清華大學 === 生物科技研究所 === 101 === Liver cancer is a slow, multi-step process. We have used the hepatitis B virus X antigen (HBx)-induced liver cancer mouse model to identify the five common regulatory genes. In which Endothelin-1 (EDN1) is up-regulated at 12-month and may regulate many downstream targets genes to promote cancer formation in 16 to 18 months. We also found hepatocellular carcinoma patients with up-regulation of three α-mannosidase genes (MAN1A1, MAN1A2, MAN1B1) compared with normal liver tissue increased more than 2 fold, while 94% of the stage I-HBV(+)-HCC patients had compared to normal liver tissue the α-mannosidase 1C is down-regulated more than 2 fold. In my thesis, I further explored the molecular mechanism of endothelin-1 and α-mannosidase 1C in the liver cancer formation.
In previous studies, EDN1 has been found high expression in many tumor tissues compared to normal tissues. Abnormal EDN1 expression implicated cell proliferation, angiogenesis, apoptosis and metastasis. Our lab had established the liver-specific edn1 transgenic fish, and found edn1 caused hyperplasia and HCC in 11 months accompanied by up-regulation of genes involved in cell cycle, proliferation, tumor markers and metastasis related genes. Using cell culture system, I continue to explore the molecular mechanisms of EDN1 in hepatocarcinogenesis. Overexpression of EDN1 in 293T cells enhanced cell proliferation, cell migration ability in vitro and in xenotransplantation assays, and was accompanied by the up-regulation of cell cycle/proliferation and migration related genes. Furthermore, the expression of UPR pathway-related mediators, such as spliced XBP1, ATF6, IRE1 and PERK, were also up-regulated in both RNA and protein level. In the presence of EDN1 or AKT inhibitor, these increased expression levels were diminished, and the migration ability enhanced by EDN1 was also disappeared, suggesting that EDN1 acts through the AKT pathway to enhance the UPR and subsequently activate the expression of downstream genes to achieve its function. Those data suggest that EDN1 plays an important role in cancer progression by activating the PI3K/AKT pathway to regulate downstream genes expression.
According to hepatitis B virus X antigen-induced hepatocellular carcinoma (HCC) mouse model in our lab, we identified α-mannosidase 1C significantly down-regulated while other three MAN1 genes (MAN1A1, MAN1A2 and MAN1B1) were up-regulated. The α-mannosidase inhibitors treatment in tumor cells, suppressing tumor cells growth and led the tumor cells to apoptosis. I found overexpression of MAN1C1 in Hep3B cells inhibits the expression of cell cycle/proliferation and migration related genes. Furthermore, the expression of UPR pathway-related mediators was affected in RNA level. Our data suggest MAN1C1 inhibit the expression of downstream genes to achieve its function.
UPR pathway-related genes have been implicated in above, that suggests the regulation of UPR pathway-related mediators is important in cancer formation; it might serve as drug target for preventing cancer formation.
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