title: TGF-β Induces Degradation of PTHrP Through Ubiquitin-Proteasome System in Hepatocellular Carcinoma.
abstract: Both transforming growth factor-β (TGF-β) 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-β are largely unknown. We hypothesized that TGF-β 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-β on protein expression and post-translational processing of PTHrP. We found that TGF-β 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-β was present in non-neoplastic liver tissue adjacent to hepatocellular carcinoma. Our findings reveal a novel mechanism whereby TGF-β may regulate PTHrP in hepatocellular carcinogenesis and lack of TGF-β 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.
authors.affiliation: 1. Medical College, Hunan Normal University, Changsha, Hunan 410013, China;
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.affiliation: 1. Medical College, Hunan Normal University, Changsha, Hunan 410013, China;
authors.forename: Guangchun
authors.initials: G
authors.lastname: He
authors.affiliation: 1. Medical College, Hunan Normal University, Changsha, Hunan 410013, China;
authors.forename: Hui
authors.initials: H
authors.lastname: Yao
authors.affiliation: 1. Medical College, Hunan Normal University, Changsha, Hunan 410013, China;
authors.forename: Liujiang
authors.initials: L
authors.lastname: Song
authors.affiliation: 2. Department of Pathology, The Affiliated Hunan Provincial Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zeng
authors.affiliation: 1. Medical College, Hunan Normal University, Changsha, Hunan 410013, China;
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Peng
authors.affiliation: 3. Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, United States of America.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rosol
authors.affiliation: 1. Medical College, Hunan Normal University, Changsha, Hunan 410013, China;
authors.forename: Xiyun
authors.initials: X
authors.lastname: Deng
keywords: Hepatocellular carcinoma; Parathyroid hormone-related protein; Proteasomal degradation.; Transforming growth factor β; Ubiquitination