Expression of transforming growth factor ?1 promotes cholangiocarcinoma development and progression.

ABSTRACT: The role of transforming growth factor beta 1 (TGF?1) in cholangiocarcinoma (CCA) initiation and growth requires further definition.We employed pharmacological and genetic approaches to inhibit or enhance TGF?1 signaling, respectively, and determine the cellular mechanisms involved.It was observed that inhibiting TGF?1 activity with short hairpin RNA (shRNA) or pharmaceutical agents suppressed CCA development and growth, whereas overexpression of TGF?1 enhanced CCA tumor size and promoted intrahepatic metastasis in a rat model. Suppression of TGF?1 activity inhibits downstream target gene expression mediated by miR-34a that includes cyclin D1, CDK6, and c-Met. In addition, "knockdown" of TGF?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?1 on cell growth, migration, cyclin D1, CDK6 and c-Met expression, suggesting that TGF?1 mediated effects occur, in part, through this miR-34a signaling pathway. Overexpression of TGF?1 was associated with CCA tumor progression.This study suggests that TGF?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.

SUBMITTER: Huang CK 

PROVIDER: S-EPMC4973469 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature