TGF-? Induces Degradation of PTHrP Through Ubiquitin-Proteasome System in Hepatocellular Carcinoma.

ABSTRACT: Both transforming growth factor-? (TGF-?) and parathyroid hormone-related protein (PTHrP) regulate important cellular processes, such as apoptosis in the development of hepatocellular carcinoma. However, the mechanisms of regulation of PTHrP by TGF-? are largely unknown. We hypothesized that TGF-? regulates the expression of PTHrP protein through a post-translational mechanism. Using hepatocellular carcinoma cell lines as the in vitro model, we investigated the effects of TGF-? on protein expression and post-translational processing of PTHrP. We found that TGF-? treatment led to protein degradation of PTHrP through the ubiquitin-proteasome-dependent pathway. We also provided evidence to show that Smurf2 was the E3 ligase responsible for the ubiquitination of PTHrP. Furthermore, using immunohistochemistry on human hepatocellular carcinoma specimens and a tissue array, we found that the expression of PTHrP was predominantly in the cancer cells, whereas the expression of TGF-? was present in non-neoplastic liver tissue adjacent to hepatocellular carcinoma. Our findings reveal a novel mechanism whereby TGF-? may regulate PTHrP in hepatocellular carcinogenesis and lack of TGF-? in hepatocellular carcinoma may promote cancer progression. Promotion of PTHrP degradation provides a novel target of therapeutic intervention to sensitize hepatocellular carcinoma cells to cytostatic and/or pro-apoptotic signals.

SUBMITTER: Li H 

PROVIDER: S-EPMC4439935 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature