RRC ID 43946
Author Zhang L, Sun H, Zhao F, Lu P, Ge C, Li H, Hou H, Yan M, Chen T, Jiang G, Xie H, Cui Y, Huang X, Fan J, Yao M, Li J.
Title BMP4 administration induces differentiation of CD133+ hepatic cancer stem cells, blocking their contributions to hepatocellular carcinoma.
Journal Cancer Res
Abstract CD133+ cancer stem cells (CSC) contribute to hepatocellular carcinoma (HCC) progression and resistance to therapy. Bone morphogenetic protein BMP4 plays an important role in hepatogenesis and hepatic stem cell differentiation, but little is known about its function in hepatic CSCs. In this study, we showed that high-dose exogenous BMP4 promotes CD133+ HCC CSC differentiation and inhibits the self-renewal, chemotherapeutic resistance, and tumorigenic capacity of these cells. Interestingly, we found that low-dose exogenous BMP4 upregulated CD133 protein expression in vitro, and endogenous BMP4 was preferentially expressed in CD133+ HCC CSCs, suggesting that low doses of BMP4 may facilitate CSC maintenance. A reduction in endogenous BMP4 levels decreased CD133 protein expression in vitro. In HCC tissues, expression of the BMP4 signaling target gene SMAD6 was positively correlated with CD133 expression. Activation of the Erk1/2 signaling pathway led to BMP4-mediated reduction in CD133 expression, which was reversed by treatment with MEK inhibitors. Taken together, our findings indicated that BMP4 might be a potent therapeutic agent in HCC that targets CSCs.
Volume 72(16)
Pages 4276-85
Published 2012-8-15
DOI 10.1158/0008-5472.CAN-12-1013
PII 0008-5472.CAN-12-1013
PMID 22773665
MeSH AC133 Antigen Antigens, CD / biosynthesis Bone Morphogenetic Protein 4 / genetics Bone Morphogenetic Protein 4 / metabolism Bone Morphogenetic Protein 4 / pharmacology* Carcinoma, Hepatocellular / drug therapy* Carcinoma, Hepatocellular / genetics Carcinoma, Hepatocellular / metabolism Carcinoma, Hepatocellular / pathology Cell Differentiation / drug effects Glycoproteins / biosynthesis Humans Liver Neoplasms / drug therapy* Liver Neoplasms / genetics Liver Neoplasms / metabolism Liver Neoplasms / pathology Mitogen-Activated Protein Kinase 1 / metabolism Mitogen-Activated Protein Kinase 3 / metabolism Neoplastic Stem Cells / drug effects* Neoplastic Stem Cells / pathology Peptides Phosphorylation Smad6 Protein / biosynthesis Smad6 Protein / genetics
IF 9.727
Times Cited 60
Human and Animal Cells