title: RhBMP-2 Activates Hippo Signaling through RASSF1 in Esophageal Cancer Cells.
abstract: Despite that recombinant human bone morphogenetic protein-2 (rhBMP-2) has been reported as a stimulatory effecter of cancer cell growth because of its characteristic like morphogen, the biological functions of rhBMP-2 in human esophageal cancer cells are unknown. The purpose of this study was to investigate whether rhBMP-2 has an inhibitory effect on the growth of human esophageal squamous carcinoma cells (ESCC). RhBMP-2 significantly inhibited proliferation of ESCC cells in a dose-dependent manner in the MTT assay. Cell cycle arrest at the G1 phase was induced 24 h after rhBMP2 treatment. RhBMP-2 also reduced cyclin D1, cyclin-dependent kinase (CDK) 4 and CDK 6 activities, and stimulated p-Smad1/5/8, p53, and p21 levels at 12 h. In contrast, rhBMP-2 diminished poly (ADP-ribose) polymerase (PARP) protein expression levels and activated cleaved PARP, cleaved caspase-7, and cleaved-caspase 9 levels in ESCC cells. In addition, rhBMP-2 increased MST1, MOB1, and p-YAP protein levels and the RASSF1 binds Mst1 more upon treatment with rhBMP2. The induced p-YAP expression in TE-8 and TE-12 cells by rhBMP-2 was reversed by the RASSF1 knockdown. In vivo study, rhBMP-2 decreased tumor volume following subcutaneous implantation and showed higher radiologic score (less bony destruction) after femoral implantation compared to those in a control group. These results suggest that rhBMP-2 inhibits rather than activates proliferation of human esophageal cancer cells which is mediated through activating the hippo signaling pathway.
authors.affiliation: Department of Physiology, Institute for Medical Sciences, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital Chonbuk National University Medical School, Jeon Ju, 561-180, Republic of Korea.
authors.forename: Soo Mi
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Department of Orthopedic Surgery, Institute for Medical Sciences, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital Chonbuk National University Medical School, Jeon Ju, 561-180, Republic of Korea.
authors.forename: Shuai
authors.initials: S
authors.lastname: Ye
authors.affiliation: Department of Biochemistry, Institute for Medical Sciences, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital Chonbuk National University Medical School, Jeon Ju, 561-180, Republic of Korea.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Rah
authors.affiliation: Department of Biochemistry, Institute for Medical Sciences, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital Chonbuk National University Medical School, Jeon Ju, 561-180, Republic of Korea.
authors.forename: Byung Hyun
authors.initials: BH
authors.lastname: Park
authors.affiliation: Department of Gastroenterology, Institute for Medical Sciences, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital Chonbuk National University Medical School, Jeon Ju, 561-180, Republic of Korea.
authors.forename: Hongen
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Orthopedic Surgery, Institute for Medical Sciences, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital Chonbuk National University Medical School, Jeon Ju, 561-180, Republic of Korea.
authors.forename: Jung-Ryul
authors.initials: JR
authors.lastname: Kim
authors.affiliation: Department of Orthopedic Surgery, Institute for Medical Sciences, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital Chonbuk National University Medical School, Jeon Ju, 561-180, Republic of Korea.
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Pathology, Institute for Medical Sciences, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital Chonbuk National University Medical School, Jeon Ju, 561-180, Republic of Korea.
authors.forename: Kyu Yun
authors.initials: KY
authors.lastname: Jang
authors.affiliation: Department of Orthopedic Surgery, Institute for Medical Sciences, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital Chonbuk National University Medical School, Jeon Ju, 561-180, Republic of Korea.
authors.forename: Kwang-Bok
authors.initials: KB
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D000090683:Hippo Signaling Pathway; D006801:Humans; D008807:Mice, Inbred BALB C; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D055396:Bone Morphogenetic Protein 2; C411762:RASSF1 protein, human; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; C499469:recombinant human bone morphogenetic protein-2; D017346:Protein Serine-Threonine Kinases