BMP9 Is a Proliferative and Survival Factor for Human Hepatocellular Carcinoma Cells

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.

Regulation of the ALK1 ligands, BMP9 and BMP10

“…BMP9 expression is increased in the tumours in the RIP-Tag2 mouse model [28], ovarian cancer cells [29] and in 15 out of 35 human hepatocellular carcinoma tissues that were investigated [30]. However, in a survey of 97 breast cancer specimens, BMP10 expression was decreased measured by both immunohistochemical staining and qPCR, and the decreased BMP10 expression was positively correlated with disease progression, bone metastasis and poor prognosis [31].…”

BMP-9 interferes with liver regeneration and promotes liver fibrosis

“…BMPs initiate signalling from the cell surface by binding to two different types of serine/threonine kinase receptors (I and II). Formation of the active ligand–receptor complex induces signal transduction pathways through phosphorylation of small mothers against decapentaplegic (SMAD) proteins, and through SMAD-independent pathways via mitogen-activated protein kinases (extracellular signal-regulated kinase, p38 mitogen-activated protein kinases, c-Jun N-terminal kinase) 5 6. BMPs can act in an autocrine or paracrine manner and the outcome is highly context dependent 7–10…”

All-trans retinoic acid restored the osteogenic ability of BMP9 in osteosarcoma through the p38 MAPK pathway

“…BMP9 has been implied in tumourigenesis (7)(8)(9)(10)(11)(12)(13)16,(19)(20)(21)(22). The proliferative effect of BMP9 on tumours varies considerably.…”

“…The proliferative effect of BMP9 on tumours varies considerably. BMP9 promotes the proliferation of ovarian cancer cells (21) and hepatocellular carcinoma cells (22), but it inhibits the proliferation of colon cancer cells (19), breast cancer cells (20) and gastric cancer cells (16). However, the proliferative effect of BMP9 on OS is unclear.…”

“…Other studies also indicated that BMP9 failed to induce osteogenic differentiation in OS (8,9,(11)(12)(13). Aberrant expression of BMP9 might result in many human tumours, such as colon cancer (19), breast cancer (20), ovarian cancer (21), hepatocellular carcinoma (22) and gastric cancer (16). These data indicate that the abnormal osteogenic differentiation related to BMP9 might be one of the determinants in the pathogenesis of OS.…”