Ectonucleoside triphosphate diphosphohydrolase type 5 (ENTPD5, also CD39L4) is a soluble enzyme that hydrolyzes purine nucleoside diphosphates. Genetic inactivation of ENTPD5 in mice (Entpd5(-/-)) resulted in 2 major histopathologic lesions: hepatopathy and aspermia. The hepatopathy was progressive and characterized by centrilobular hepatocyte hypertrophy, oval cell proliferation, bile staining of Kupffer cells, and hepatocyte degeneration with increasing incidence and severity of degenerative lesions, development of multiple foci of cellular alteration, and hepatocellular neoplasia with age. Greatly increased proliferation of hepatocytes in young adult as well as aged Entpd5(-/-) mice was demonstrated by Ki67 immunohistochemistry and 5'-bromo-3'-deoxyuridine incorporation. Of 15 Entpd5(-/-) mice between 44 and 69 weeks of age, all showed foci of cellular alteration in the liver, and at least 6 of 15 developed hepatocellular carcinoma (HCC), hepatocellular adenoma, or both. Significantly, none of these lesions were observed in 13 wild-type Entpd5(+/+) littermates. These findings, combined with the historically low incidence (about 5%) of HCC in mice up to 2 years of age with the same genetic background, strongly suggest that loss of Entpd5 promotes hepatocellular neoplasia in mice. In humans, ENTPD5 has been found to be identical to the PCPH proto-oncogene, and dysregulation of this gene has been demonstrated in some human cancers. This mouse model could contribute to the understanding of the influence of ENTPD5/PCPH on cellular proliferation and neoplasia.
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