Oncotarget

Research Papers:

Tumor suppressive microRNA-1285 regulates novel molecular targets: Aberrant expression and functional significance in renal cell carcinoma

Hideo Hidaka, Naohiko Seki, Hirofumi Yoshino, Takeshi Yamasaki, Yasutoshi Yamada, Nijiro Nohata, Miki Fuse, Masayuki Nakagawa and Hideki Enokida _

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Oncotarget. 2012; 3:44-57. https://doi.org/10.18632/oncotarget.417

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Abstract

Hideo Hidaka1,*, Naohiko Seki2,*, Hirofumi Yoshino1, Takeshi Yamasaki1, Yasutoshi Yamada1, Nijiro Nohata2, Miki Fuse2, Masayuki Nakagawa1 and Hideki Enokida1

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

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

* Denotes equal contribution

Received: December 31, 2011; Accepted: January 21, 2012; Published: January 30, 2012;

Keywords: microRNA, expression signature, miR-1285, tumor suppressor, renal cell carcinoma, transglutaminase 2

Correspondence:

Hideki Enokida, email:

Abstract

MicroRNAs (miRNA) are non-coding RNAs, approximately 22 nucleotides in length, which function as post-transcriptional regulators.  A large body of evidence indicates that miRNAs regulate the expression of cancer-related genes involved in proliferation, migration, invasion, and metastasis. The aim of this study was to identify novel cancer networks in renal cell carcinoma (RCC) based on miRNA expression signatures obtained from RCC clinical specimens. Expression signatures revealed that 103 miRNAs were significantly downregulated (< 0.5-fold change) in RCC specimens. Functional screening (cell proliferation assays) was performed to identify tumor suppressive activities of 20 downregulated miRNAs. Restoration of mature miRNAs in cancer cells showed that 14 miRNAs (miR-1285, miR-206, miR-1, miR-135a, miR-429, miR-200c, miR-1291, miR-133b, miR-508-3p, miR-360-3p, miR-509-5p, miR-218, miR-335, miR-1255b and miR-1285) markedly inhibited cancer cell proliferation, suggesting that these miRNAs were candidate tumor suppressive miRNAs in RCC. We focused on miR-1285 because it significantly inhibited cancer cell proliferation, invasion, and migration following its transfection. We addressed miR-1285-regulated cancer networks by using genome-wide gene expression analysis and bioinformatics. The data showed that transglutaminase 2 (TGM2) was directly regulated by miR-1285. Silencing of the target gene demonstrated significant inhibition of cell proliferation and invasion in the RCC cells. Furthermore, immunohistochemistry showed that TGM2 expression levels in RCC specimens were significantly higher than those in normal renal tissues. Downregulation of tumor suppressive miR-1285, which targets oncogenic genes including TGM2, might contribute to RCC development. Thus, miR-1285 modulates a novel molecular target and provides new insights into potential mechanisms of RCC oncogenesis.


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