Expression of transforming growth factor β1 promotes cholangiocarcinoma development and progression
| Autor: | Hironori Koga, Miran Kim, Jing Zou, Jack R. Wands, Rolf I. Carlson, Chiung-Kuei Huang, Arihiro Aihara, Tunan Yu, Yoshifumi Iwagami, Sarah Casulli |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Cancer Research Transfection Article Cholangiocarcinoma Transforming Growth Factor beta1 Small hairpin RNA 03 medical and health sciences 0302 clinical medicine Cyclin D1 Cell Movement Cell Line Tumor Animals Humans Cell Proliferation Gene knockdown biology Cyclin-Dependent Kinase 6 Neoplasms Experimental Transforming growth factor beta Proto-Oncogene Proteins c-met Molecular biology Rats Inbred F344 Rats Up-Regulation Gene Expression Regulation Neoplastic MicroRNAs 030104 developmental biology Bile Duct Neoplasms Oncology MicroRNA 34a Tumor progression 030220 oncology & carcinogenesis Disease Progression biology.protein Cancer research RNA Interference Cyclin-dependent kinase 6 Signal Transduction Transforming growth factor |
| Zdroj: | Cancer Letters. 380:153-162 |
| ISSN: | 0304-3835 |
| DOI: | 10.1016/j.canlet.2016.05.038 |
| Popis: | Background and aims The role of transforming growth factor beta 1 (TGFβ1) in cholangiocarcinoma (CCA) initiation and growth requires further definition. Methods We employed pharmacological and genetic approaches to inhibit or enhance TGFβ1 signaling, respectively, and determine the cellular mechanisms involved. Results 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. Conclusions 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. |
| Databáze: | OpenAIRE |
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