title: BMP4 administration induces differentiation of CD133+ hepatic cancer stem cells, blocking their contributions to hepatocellular carcinoma.
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.
authors: State Key Laboratrory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors: Lixing
authors: L
authors: Zhang
authors: Hefen
authors: H
authors: Sun
authors: Fangyu
authors: F
authors: Zhao
authors: Ping
authors: P
authors: Lu
authors: Chao
authors: C
authors: Ge
authors: Hong
authors: H
authors: Li
authors: Helei
authors: H
authors: Hou
authors: Mingxia
authors: M
authors: Yan
authors: Taoyang
authors: T
authors: Chen
authors: Guoping
authors: G
authors: Jiang
authors: Haiyang
authors: H
authors: Xie
authors: Ying
authors: Y
authors: Cui
authors: Xiaowu
authors: X
authors: Huang
authors: Jia
authors: J
authors: Fan
authors: Ming
authors: M
authors: Yao
authors: Jinjun
authors: J
authors: Li
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000096:biosynthesis; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D010455:Peptides; D010766:Phosphorylation; D051905:Smad6 Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C497802:SMAD6 protein, human; D051905:Smad6 Protein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3