Expression of transforming growth factor β1 promotes cholangiocarcinoma development and progression

Background and aims: The role of transforming growth factor beta 1 (TGF beta 1) in cholangiocarcinoma (CCA) initiation and growth requires further definition. Methods: We employed pharmacological and genetic approaches to inhibit or enhance TGF beta 1 signaling, respectively, and determine the cellular mechanisms involved. Results: It was observed that inhibiting TGF beta 1 activity with short hairpin RNA (shRNA) or pharmaceutical agents suppressed CCA development and growth, whereas overexpression of TGF beta 1 enhanced CCA tumor size and promoted intrahepatic metastasis in a rat model. Suppression of TGF beta 1 activity inhibits downstream target gene expression mediated by miR-34a that includes cyclin D1, CDK6, and c-Met. In addition, knockdown of TGF beta 1 expression revealed a miR-34a positive feedback mechanism for enhanced p21 expression in CCAs. A miR-34a inhibitor reversed the effects of knocking down TGF beta 1 on cell growth, migration, cyclin D1, CDK6 and c-Met expression, suggesting that TGF beta 1 mediated effects occur, in part, through this miR-34a signaling pathway. Overexpression of TGF beta 1 was associated with CCA tumor progression. Conclusions: This study suggests that TGF beta 1 is involved in CCA tumor progression and participates through miR-34a mediated downstream cascades, and is a target to inhibit CCA development and growth. (C) 2016 Elsevier Ireland Ltd. All rights reserved.