title: Expression of transforming growth factor β1 promotes cholangiocarcinoma development and progression.
abstract: The role of transforming growth factor beta 1 (TGFβ1) in cholangiocarcinoma (CCA) initiation and growth requires further definition.
  
  
  
  We employed pharmacological and genetic approaches to inhibit or enhance TGFβ1 signaling, respectively, and determine the cellular mechanisms involved.
  
  
  
  It was observed that inhibiting TGFβ1 activity with short hairpin RNA (shRNA) or pharmaceutical agents suppressed CCA development and growth, whereas overexpression of TGFβ1 enhanced CCA tumor size and promoted intrahepatic metastasis in a rat model. Suppression of TGFβ1 activity inhibits downstream target gene expression mediated by miR-34a that includes cyclin D1, CDK6, and c-Met. In addition, "knockdown" of TGFβ1 expression revealed a miR-34a positive feedback mechanism for enhanced p21 expression in CCAs. A miR-34a inhibitor reversed the effects of "knocking down" TGFβ1 on cell growth, migration, cyclin D1, CDK6 and c-Met expression, suggesting that TGFβ1 mediated effects occur, in part, through this miR-34a signaling pathway. Overexpression of TGFβ1 was associated with CCA tumor progression.
  
  
  
  This study suggests that TGFβ1 is involved in CCA tumor progression and participates through miR-34a mediated downstream cascades, and is a target to inhibit CCA development and growth.
authors.affiliation: Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI 02903, USA.
authors.forename: Chiung-Kuei
authors.initials: CK
authors.lastname: Huang
authors.affiliation: Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI 02903, USA.
authors.forename: Arihiro
authors.initials: A
authors.lastname: Aihara
authors.affiliation: Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI 02903, USA.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Iwagami
authors.affiliation: Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI 02903, USA.
authors.forename: Tunan
authors.initials: T
authors.lastname: Yu
authors.affiliation: Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI 02903, USA.
authors.forename: Rolf
authors.initials: R
authors.lastname: Carlson
authors.affiliation: Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Koga
authors.affiliation: Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI 02903, USA.
authors.forename: Miran
authors.initials: M
authors.lastname: Kim
authors.affiliation: Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI 02903, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zou
authors.affiliation: Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI 02903, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Casulli
authors.affiliation: Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI 02903, USA. Electronic address: Jack_Wands_MD@brown.edu.
authors.forename: Jack R
authors.initials: JR
authors.lastname: Wands
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C530106:Ccnd1 protein, rat; C560944:MIRN34 microRNA, rat; D035683:MicroRNAs; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D019938:Cyclin D1; D019859:Proto-Oncogene Proteins c-met; C495913:Cdk6 protein, rat; D051361:Cyclin-Dependent Kinase 6
keywords: Bile duct tumor; Liver fibrosis; TGFβ1 inhibitor; miRNA-34a