The functional significance of miR-1 and miR-133a in renal cell carcinoma

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• 作者：Kazumori Kawakami^a ; Hideki Enokida^a ; ^{enokida@m.kufm.kagoshima-u.ac.jp} ; Takeshi Chiyomaru^a ; Shuichi Tatarano^a ; Hirofumi Yoshino^a ; Ichiro Kagara^a ; Takenari Gotanda^a ; Tokushi Tachiwada^a ; Kenryu Nishiyama^a ; Nijiro Nohata^b ; Naohiko Seki^b ; Masayuki Nakagawa^a
• 关键词：TAGLN2 ; MicroRNA ; MiR-1 ; MiR-133a ; Renal cell cancer
• 刊名：European Journal of Cancer
• 出版年：2012
• 出版时间：April, 2012
• 年：2012
• 卷：48
• 期：6
• 页码：827-836
• 全文大小：1079 K

文摘

Purpose

The aim of this study was to find a novel molecular network involved in renal cell carcinoma (RCC) development through investigating the functions of miR-1 and miR-133a and their target genes.

Methods

We checked the expression levels of miR-1 and miR-133a in RCC cell lines and specimens (N = 40) using real time RT-PCR. MiR-1 and miR-133a transfectants were subjected to a gain-of-function study to identify the functions of the miRNAs. To find the target genes of the miRNAs, we analysed the gene expression profile of their transfectants and performed a luciferase reporter assay. mRNA expression levels of the candidate target gene in the clinical specimens were examined, and loss-of-function studies were performed.

Results

The expression levels of miR-1 and miR-133a were significantly suppressed in RCC cell lines and specimens. Ectopic restoration of miR-1 and miR-133a showed significant inhibition of cell proliferation and invasion, and moreover, revealed induction of apoptosis and cell cycle arrest. The luciferase assay revealed transgelin-2 (TAGLN2), selected as a target gene for miR-1 and miR-133a on the basis of the gene expression profile, to be directly regulated by both miR-1 and miR-133a. The loss-of-function studies showed significant inhibitions of cell proliferation and invasion in the si-TAGLN2 transfectant. The expression level of TAGLN2 mRNA was significantly up-regulated in the RCC specimens; in addition, there was a statistically significant inverse correlation between TAGLN2 and miR-1 and miR-133a expression.

Conclusions

Our data indicate that up-regulation of the oncogenic TAGLN2 was due to down-regulation of tumour-suppressive miR-1 and miR-133a in human RCC.