Dual regulation of receptor tyrosine kinase genes EGFR and c-Met by the tumor-suppressive microRNA-23b/27b cluster in bladder cancer

Chiyomaru,Takeshi; Seki,Naohiko; Inoguchi,Satoru; Ishihara,Tomoaki; Mataki,Hiroko; Matsushita,Ryosuke; Goto,Yusuke; Nishikawa,Rika; Tatarano,Shuichi; Itesako,Toshihiko; Nakagawa,Masayuki; Enokida,Hideki

doi:10.3892/ijo.2014.2752

Dual regulation of receptor tyrosine kinase genes EGFR and c-Met by the tumor-suppressive microRNA-23b/27b cluster in bladder cancer

Authors:
- Takeshi Chiyomaru
- Naohiko Seki
- Satoru Inoguchi
- Tomoaki Ishihara
- Hiroko Mataki
- Ryosuke Matsushita
- Yusuke Goto
- Rika Nishikawa
- Shuichi Tatarano
- Toshihiko Itesako
- Masayuki Nakagawa
- Hideki Enokida
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Affiliations: Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan, Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan, Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
Published online on: November 14, 2014 https://doi.org/10.3892/ijo.2014.2752
Pages: 487-496
Copyright: © Chiyomaru et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Recent clinical trials of chemotherapeutics for advanced bladder cancer (BC) have shown limited benefits. Therefore, new prognostic markers and more effective treatment strategies are required. One approach to achieve these goals is through the analysis of RNA networks. Our recent studies of microRNA (miRNA) expression signatures revealed that the microRNA-23b/27b (miR-23b/27b) cluster is frequently downregulated in various types of human cancers. However, the functional role of the miR-23b/27b cluster in BC cells is still unknown. Thus, the aim of the present study was to investigate the functional significance of the miR-23b/27b cluster and its regulated molecular targets, with an emphasis on its contributions to BC oncogenesis and metastasis. The expression levels of the miR-23b/27b cluster were significantly reduced in BC clinical specimens. Restoration of mature miR-23b or miR-27b miRNAs significantly inhibited cancer cell migration and invasion, suggesting that these clustered miRNAs function as tumor suppressors. Gene expression data and in silico analysis demonstrated that the genes coding for the epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-Met) were potential targets of the miR-23b/27b cluster. Luciferase reporter assays and western blotting demonstrated that EGFR and c-Met receptor trypsine kinases were directly regulated by these clustered miRNAs. We conclude that the decreased expression of the tumor-suppressive miR-23b/27b cluster enhanced cancer cell proliferation, migration and invasion in BC through direct regulation of EGFR and c-Met signaling pathways. Our data on RNA networks regulated by tumor-suppressive miR-23b/27b provide new insights into the potential mechanisms of BC oncogenesis and metastasis.

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