title: Bone morphogenetic protein-9 is a potent growth inhibitor of hepatocellular carcinoma and reduces the liver cancer stem cells population.
abstract: The biological role of BMP-9 signaling in liver cancer remains dubious. To explore the potential use of BMP-9 signaling for anti-cancer therapy, we used recombinant human BMP-9, which we referred to as MB109, to study the effect on growth of fifteen hepatocellular carcinoma (HCC) cell lines. MB109 effectively inhibits the proliferation of nine HCC cells in vitro. The anti-proliferative effect was found to be induced by turning on p21 signaling, which caused survivin suppression and G0/G1 cell cycle arrest. ID3 was identified to be the mediator of the MB109-induced p21 expression. Blocking the activity of p38 MAPK diminished ID3 and p21 expression, indicating that MB109 signals through a p38 MAPK/ID3/p21 pathway to arrest cell cycle progression. Moreover, prolonged MB109 treatment suppressed the expression of five prominent liver cancer stem cell (LCSC) markers, including CD44, CD90, AFP, GPC3 and ANPEP. Xenograft model confirmed the anti-tumor and LCSC-suppression capability of MB109 in vivo. Contrary to ongoing efforts of suppressing BMP-9 signaling to inhibit angiogenesis of cancer tissue, these results demonstrate an unexpected therapeutic potential of MB109 to stimulate BMP-9 signaling for anti-cancer therapies.
authors.affiliation: Protein Engineering Laboratory, Joint Center for Biosciences, Songdo Smart Valley, Yeonsu-gu, Incheon 406-840, South Korea.|Current address: Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Jae Woo
authors.initials: JW
authors.lastname: Jung
authors.affiliation: Protein Engineering Laboratory, Joint Center for Biosciences, Songdo Smart Valley, Yeonsu-gu, Incheon 406-840, South Korea.
authors.forename: So-Mi
authors.initials: SM
authors.lastname: Yoon
authors.affiliation: Protein Engineering Laboratory, Joint Center for Biosciences, Songdo Smart Valley, Yeonsu-gu, Incheon 406-840, South Korea.
authors.forename: Subin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Protein Engineering Laboratory, Joint Center for Biosciences, Songdo Smart Valley, Yeonsu-gu, Incheon 406-840, South Korea.
authors.forename: Yun-Hui
authors.initials: YH
authors.lastname: Jeon
authors.affiliation: Protein Engineering Laboratory, Joint Center for Biosciences, Songdo Smart Valley, Yeonsu-gu, Incheon 406-840, South Korea.
authors.forename: Byung-Hak
authors.initials: BH
authors.lastname: Yoon
authors.affiliation: Department of New Drug Development, School of Medicine, Inha University, Incheon 400-712, South Korea.
authors.forename: Su-Geun
authors.initials: SG
authors.lastname: Yang
authors.affiliation: Department of New Drug Development, School of Medicine, Inha University, Incheon 400-712, South Korea.
authors.forename: Min Kyoung
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Protein Engineering Laboratory, Joint Center for Biosciences, Songdo Smart Valley, Yeonsu-gu, Incheon 406-840, South Korea.|Drug Discovery Collaboratory, University of California, San Diego, La Jolla, CA 92037, United States of America.
authors.forename: Senyon
authors.initials: S
authors.lastname: Choe
authors.affiliation: Protein Engineering Laboratory, Joint Center for Biosciences, Songdo Smart Valley, Yeonsu-gu, Incheon 406-840, South Korea.|Drug Discovery Collaboratory, University of California, San Diego, La Jolla, CA 92037, United States of America.|Current address: Polaris Pharmaceuticals, Inc., San Diego, CA 92121, United States of America.
authors.forename: Mario Meng-Chiang
authors.initials: MM
authors.lastname: Kuo
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D055427:Growth Differentiation Factor 2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D055427:Growth Differentiation Factor 2; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; D016212:Transforming Growth Factor beta; C075640:ID3 protein, human; D048051:p38 Mitogen-Activated Protein Kinases
keywords: TGF-beta; bone morphogenetic protein 9; hepatocellular carcinoma; liver cancer stem cell; p21