BMP9 is a proliferative and survival factor for human hepatocellular carcinoma cells.
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.
Dep. Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain. bm.herrera@farm.ucm.es
Blanca
B
Herrera
María
M
García-Álvaro
Silvia
S
Cruz
Peter
P
Walsh
Margarita
M
Fernández
Cesáreo
C
Roncero
Isabel
I
Fabregat
Aránzazu
A
Sánchez
Gareth J
GJ
Inman
D030301:Activin Receptors, Type II / Q000737:chemistry / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication / Q000187:drug effects; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002452:Cell Count; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors / Q000378:metabolism* / Q000494:pharmacology; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D044967:Serum; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism
C525887:GDF2 protein, human; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D051785:Smad Proteins; D030301:Activin Receptors, Type II; D052004:Bone Morphogenetic Protein Receptors