BMP9 is a proliferative and survival factor for human hepatocellular carcinoma cells

Herrera, B., García-Álvaro, M., Cruz, S., Walsh, P., Fernández, M., Roncero, C., Fabregat, I., Sánchez, A. and Inman, G. J. (2013) BMP9 is a proliferative and survival factor for human hepatocellular carcinoma cells. PLoS ONE, 8(7), e69535. (doi: 10.1371/journal.pone.0069535) (PMID:23936038) (PMCID:PMC3720667)

Abstract

TGF-β family members play a relevant role in tumorigenic processes, including hepatocellular carcinoma (HCC), but a specific implication of the Bone Morphogenetic Protein (BMP) subfamily is still unknown. Although originally isolated from fetal liver, little is known about BMP9, a BMP family member, and its role in liver physiology and pathology. Our results show that BMP9 promotes growth in HCC cells, but not in immortalized human hepatocytes. In the liver cancer cell line HepG2, BMP9 triggers Smad1,5,8 phosphorylation and inhibitor of DNA binding 1 (Id1) expression up- regulation. Importantly, by using chemical inhibitors, ligand trap and gene silencing approaches we demonstrate that HepG2 cells autocrinely produce BMP9 that supports their proliferation and anchorage independent growth. Additionally, our data reveal that in HepG2 cells BMP9 triggers cell cycle progression, and strikingly, completely abolishes the increase in the percentage of apoptotic cells induced by long-term incubation in low serum. Collectively, our data unveil a dual role for BMP9, both promoting a proliferative response and exerting a remarkable anti-apoptotic function in HepG2 cells, which result in a robust BMP9 effect on liver cancer cell growth. Finally, we show that BMP9 expression is increased in 40% of human HCC tissues compared with normal human liver as revealed by immunohistochemistry analysis, suggesting that BMP9 signaling may be relevant during hepatocarcinogenesis in vivo. Our findings provide new clues for a better understanding of BMPs contribution, and in particular BMP9, in HCC pathogenesis that may result in the development of effective and targeted therapeutic interventions.

• Item Type: Articles
• Additional Information: M. Garcı´a-A´ lvaro is the recipient of a research assistant contract (grant S2010/BMD-2402, Comunidad de Madrid, Spain). This work has been supported by the Association for International Cancer Research, Cancer Research UK, Tenovus Scotland and the Ninewells Cancer Campaign, UK (P.W and G.J.I.); and by a research grant from the FIS-ISCIII’s (Health Research Fund –Institute of Health Carlos III, Spain). The work was also supported by Competitive Research Funding Programme (Ref. PI10/00274) to B.H.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Inman, Professor Gareth
• Authors: Herrera, B., García-Álvaro, M., Cruz, S., Walsh, P., Fernández, M., Roncero, C., Fabregat, I., Sánchez, A., and Inman, G. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Copyright Holders: Copyright © 2013 Herrera et al.
• First Published: First published in PLoS ONE 8(7):e69535
• Publisher Policy: Reproduced under a Creative Commons License