title: The activation of MEK/ERK signaling pathway by bone morphogenetic protein 4 to increase hepatocellular carcinoma cell proliferation and migration.
abstract: Hepatocellular carcinoma (HCC) is one of the most common visceral malignancies worldwide, with a very high incidence and poor prognosis. Bone morphogenesis protein 4 (BMP4), which belongs to the TGF-β superfamily of proteins, is a multifunctional cytokine, which exerts its biologic effects through SMAD- and non-SMAD-dependent pathways, and is also known to be involved in human carcinogenesis. However, the effects of the BMP4 signaling in liver carcinogenesis are not yet clearly defined. Here, we first show that BMP4 and its receptor, BMPR1A, are overexpressed in a majority of primary HCCs and that it promotes the growth and migration of HCC cell lines in vitro. We also establish that BMP4 can induce HCC cyclin-dependent kinase (CDK)1 and cyclin B1 upregulation to accelerate cell-cycle progression. Our study indicates that the induction of HCC cell proliferation is independent of the SMAD signaling pathway, as Smad4 knockdown of HCC cell lines still leads to the upregulation of CDK1 and cyclin B1 expression after BMP4 treatment. Using mitogen-activated protein/extracellular signal-regulated kinase (MEK) selective inhibitors, the induction of CDK1, cyclin B1 mRNA and protein were shown to be dependent on the activation of MEK/extracellular signal-regulated kinase (ERK) signaling. In vivo xenograft studies confirmed that the BMPR1A-knockdown cells were significantly less tumorigenic than the control groups. Our findings show that the upregulation of BMP4 and BMPR1A in HCC promotes the proliferation and metastasis of HCC cells and that CDK1 and cyclin B1 are important SMAD-independent molecular targets in BMP4 signaling pathways, during the HCC tumorigenesis. It is proposed that BMP4 signaling pathways may have potential as new therapeutic targets in HCC treatment.
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
authors.forename: Chiang-Yen
authors.initials: CY
authors.lastname: Chiu
authors.forename: Kung-Kai
authors.initials: KK
authors.lastname: Kuo
authors.forename: Tzu-Lei
authors.initials: TL
authors.lastname: Kuo
authors.forename: King-The
authors.initials: KT
authors.lastname: Lee
authors.forename: Kuang-Hung
authors.initials: KH
authors.lastname: Cheng
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D051901:Smad4 Protein / Q000172:deficiency / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; C534699:CCNB1 protein, human; D056744:Cyclin B1; D051901:Smad4 Protein; D016203:CDC2 Protein Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D052005:Bone Morphogenetic Protein Receptors, Type I; D020929:Mitogen-Activated Protein Kinase Kinases