J Cancer 2015; 6(6):511-518. doi:10.7150/jca.10830
TGF-β Induces Degradation of PTHrP Through Ubiquitin-Proteasome System in Hepatocellular Carcinoma
1. Medical College, Hunan Normal University, Changsha, Hunan 410013, China;
2. Department of Pathology, The Affiliated Hunan Provincial Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China.
3. Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, United States of America.
* These authors contributed equally to this work.
Li H, He G, Yao H, Song L, Zeng L, Peng X, Rosol TJ, Deng X. TGF-β Induces Degradation of PTHrP Through Ubiquitin-Proteasome System in Hepatocellular Carcinoma. J Cancer 2015; 6(6):511-518. doi:10.7150/jca.10830. Available from http://www.jcancer.org/v06p0511.htm
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.
Keywords: Transforming growth factor β, Parathyroid hormone-related protein, Hepatocellular carcinoma, Ubiquitination, Proteasomal degradation.