MiR-145 negatively regulates Warburg effect by silencing KLF4 and PTBP1 in bladder cancer cells
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Koichiro Minami1,2, Kohei Taniguchi1,3, Nobuhiko Sugito1, Yuki Kuranaga1, Teruo Inamoto2, Kiyoshi Takahara2, Tomoaki Takai2, Yuki Yoshikawa1,2, Satoshi Kiyama2, Yukihiro Akao1, Haruhito Azuma2
1United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan
2Department of Urology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
3Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
Yukihiro Akao, email: [email protected]
Keywords: miR-145, Warburg effect, KLF4, bladder cancer
Received: January 29, 2016 Accepted: March 15, 2017 Published: March 23, 2017
The Warburg effect is a well-known feature in cancer-specific metabolism. We previously reported on the role of microRNA (miR)-145 as a tumor-suppressor in human bladder cancer (BC) cells. In this study, we reveal that miR-145 decreases the Warburg effect by silencing KLF4 in BC cells. The expression levels of miR-145 were significantly lower in clinical BC samples and BC cell lines compared to those in normal tissues and HUC cells. Luciferase assay results showed that miR-145 directly bound to 3′UTR of KLF4, which was shown to be overexpressed in the clinical BC samples using Western blot analysis and immunohistochemistry. Remarkable growth inhibition and apoptosis were induced by the ectopic expression of miR-145 or by the gene silencing of KLF4 (siR-KLF4). Also, Warburg effect-related genes such as PTBP1/PKMs were regulated by the transfection of BC cells with miR-145 or siR-KLF4. These results thus indicate that the miR-145/KLF4/PTBP1/PKMs axis is one of the critical pathways that maintain the Warburg effect in BC carcinogenesis. MiR-145 perturbed the Warburg effect by suppressing the KLF4/PTBP1/PKMs pathway in BC cells, resulting in significant cell growth inhibition.
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