The parkin was first identified as a gene implicated in autosomal recessive juvenile Parkinsonism. Deregulation of the parkin gene, however, has been observed in various human cancers, suggesting that the parkin gene may be important in tumorigenesis. To gain insight into the physiologic role of parkin, we generated parkin−/− mice lacking exon 3 of the parkin gene. We demonstrated here that parkin−/− mice had enhanced hepatocyte proliferation and developed macroscopic hepatic tumors with the characteristics of hepatocellular carcinoma. Microarray analyses revealed that parkin deficiency caused the alteration of gene expression profiles in the liver. Among them, endogenous follistatin is commonly upregulated in both nontumorous and tumorous liver tissues of parkin-deficient mice. Parkin deficiency resulted in suppression of caspase activation and rendered hepatocytes resistant to apoptosis in a follistatin-dependent manner. These results suggested that parkin deficiency caused enhanced hepatocyte proliferation and resistance to apoptosis, resulting in hepatic tumor development, partially through the upregulation of endogenous follistatin. The finding that parkin-deficient mice are susceptible to hepatocarcinogenesis provided the first evidence showing that parkin is indeed a tumor suppressor gene.
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We thank Dr T Fukushima for flow cytometric analysis, and Dr H Hiai for useful comments on histological study. This work was supported by Grants-in-Aid for Scientific Research 16017240, 15209024 and 15659169 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and Grant-in-Aid for Research on Measures for Intractable Diseases, and Research on Advanced Medical Technology from the Ministry of Health, Labor, and Welfare, Japan.
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Fujiwara, M., Marusawa, H., Wang, H. et al. Parkin as a tumor suppressor gene for hepatocellular carcinoma. Oncogene 27, 6002–6011 (2008). https://doi.org/10.1038/onc.2008.199
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