Parkin as a tumor suppressor gene for hepatocellular carcinoma

Abstract

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 parkinÀ/À mice lacking exon 3 of the parkin gene. We demonstrated here that parkinÀ/À 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 parkindeficient 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 parkindeficient mice are susceptible to hepatocarcinogenesis provided the first evidence showing that parkin is indeed a tumor suppressor gene.

Attenuation of proteolysis‐mediated cyclin E regulation by alternatively spliced Parkin in human colorectal cancers

“…We, recently, reported that Parkin-deficient mice lacking exon 3 of the Parkin gene are susceptible to liver carcinogenesis, providing the first evidence that Parkin is a tumor suppressor gene. 19 Consistent with our findings, a high frequency of loss of heterozygosity or deletions spanning the Parkin gene has been detected in various human cancers. [9][10][11][12][13][14][15][16][17][18] In the present study, we demonstrated that Parkin expression is induced in response to growth signaling, and is involved in the proteolytic degradation of cyclin E protein in colonic epithelial cells.…”

“…[16][17][18] We recently demonstrated that Parkin-deficient mice lacking exon 3 of the Parkin gene developed hepatocellular carcinoma, whereas Parkin -/-mice were neurologically normal with no obvious neuropathologic changes. 19 Further, the loss of Parkin expression contributes to the overproliferation of hepatocytes leading to hepatomegaly, suggesting a critical role for Parkin in the regulation of hepatocyte proliferation. 19 These observations suggest that Parkin has a role as a tumor suppressor and may be involved in cell cycle regulation in epithelial cells.…”

“…19 Further, the loss of Parkin expression contributes to the overproliferation of hepatocytes leading to hepatomegaly, suggesting a critical role for Parkin in the regulation of hepatocyte proliferation. 19 These observations suggest that Parkin has a role as a tumor suppressor and may be involved in cell cycle regulation in epithelial cells.…”

“…19 Further, the loss of Parkin expression contributes to the overproliferation of hepatocytes leading to hepatomegaly, suggesting a critical role for Parkin in the regulation of hepatocyte proliferation. 19 These observations suggest that Parkin has a role as a tumor suppressor and may be involved in cell cycle regulation in epithelial cells.Deregulation of the cell cycle, specifically the G1 and S phases, is a hallmark of human cancers, and cyclin E amplification and overexpression are observed in various human cancers. 20 One thing to be noted is that cyclin E protein is accumulated in the tumor cells in a considerable proportion of colorectal cancers.…”

Chronic Deletion and Acute Knockdown of Parkin Have Differential Responses to Acetaminophen-induced Mitophagy and Liver Injury in Mice

“…Parkin KO mice have previously been shown to have increased proliferation leading to the eventual development of hepatocellular carcinoma at 18 months (32,33). Therefore, we evaluated proliferation levels in WT and Parkin KO mice after APAP treatment to determine whether greater levels of hepatocyte proliferation could be an additional mechanism of protection against APAPinduced liver injury in KO mice.…”