Research Papers:

Regulation of UHRF1 by dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p): inhibition of bladder cancer cell aggressiveness

Ryosuke Matsushita, Hirofumi Yoshino, Hideki Enokida, Yusuke Goto, Kazutaka Miyamoto, Masaya Yonemori, Satoru Inoguchi, Masayuki Nakagawa and Naohiko Seki _

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Oncotarget. 2016; 7:28460-28487. https://doi.org/10.18632/oncotarget.8668

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Ryosuke Matsushita1, Hirofumi Yoshino1, Hideki Enokida1, Yusuke Goto2, Kazutaka Miyamoto1, Masaya Yonemori1, Satoru Inoguchi1, Masayuki Nakagawa1, Naohiko Seki2

1Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan

2Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan

Correspondence to:

Naohiko Seki, e-mail: [email protected]

Keywords: miR-145-5p, miR-145-3p, tumor-suppressor, UHRF1, bladder cancer

Received: February 22, 2016     Accepted: March 28, 2016     Published: April 09, 2016


In microRNA (miRNA) biogenesis, the guide-strand of miRNA integrates into the RNA induced silencing complex (RISC), whereas the passenger-strand is inactivated through degradation. Analysis of our miRNA expression signature of bladder cancer (BC) by deep-sequencing revealed that microRNA (miR)-145-5p (guide-strand) and miR-145-3p (passenger-strand) were significantly downregulated in BC tissues. It is well known that miR-145-5p functions as a tumor suppressor in several types of cancer. However, the impact of miR-145-3p on cancer cells is still ambiguous. The aim of the present study was to investigate the functional significance of miR-145-3p and BC oncogenic pathways and targets regulated by miR-145-5p/miR-145-3p. Ectopic expression of either miR-145-5p or miR-145-3p in BC cells significantly suppressed cancer cell growth, migration and invasion and it also induced apoptosis. The gene encoding ubiquitin-like with PHD and ring finger domains 1 (UHRF1) was a direct target of these miRNAs. Silencing of UHRF1 induced apoptosis and inhibited cancer cell proliferation, migration, and invasion in BC cells. In addition, overexpressed UHRF1 was confirmed in BC clinical specimens, and the high UHRF1 expression group showed a significantly poorer cause specific survival rate in comparison with the low expression group. Taken together, our present data demonstrated that both strands of miR-145 (miR-145-5p: guide-strand and miR-145-3p: passenger-strand) play pivotal roles in BC cells by regulating UHRF1. The identification of the molecular target of a tumor suppressive miRNAs provides novel insights into the potential mechanisms of BC oncogenesis and suggests novel therapeutic strategies.

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