Open AccessTumor‐suppressive micro RNA ‐135a inhibits cancer cell proliferation by targeting the c‐ MYC oncogene in renal cell carcinoma
Author(s) -
Yamada Yasutoshi,
Hidaka Hideo,
Seki Naohiko,
Yoshino Hirofumi,
Yamasaki Takeshi,
Itesako Toshihiko,
Nakagawa Masayuki,
Enokida Hideki
Publication year - 2013
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12072
Subject(s) - cancer cell , biology , cancer research , cell cycle , gene , cell growth , cell culture , cancer , oncogene , cell , metastasis , downregulation and upregulation , rna , microrna , microbiology and biotechnology , genetics
Recently, many studies have suggested that micro RNA s (mi RNA s) are involved in cancer cell development, invasion, and metastasis of various types of human cancers. In a previous study, mi RNA expression signatures from renal cell carcinoma ( RCC ) revealed that expression of micro RNA ‐135a ( miR‐135a ) was significantly reduced in cancerous tissues. The aim of this study was to investigate the functional significance of miR‐135a and to identify miR‐135a ‐mediated molecular pathways in RCC cells. Restoration of mature miR‐135a significantly inhibited cancer cell proliferation and induced G 0 /G 1 arrest in the RCC cell lines caki2 and A498, suggesting that miR‐135a functioned as a potential tumor suppressor. We then examined miR‐135a ‐mediated molecular pathways using genome‐wide gene expression analysis and in silico analysis. A total of 570 downregulated genes were identified in miR‐135a transfected RCC cell lines. To investigate the biological significance of potential miR‐135a ‐mediated pathways, we classified putative miR‐135a ‐regulated genes according to the Kyoto Encyclopedia of Genes and Genomics pathway database. From our in silico analysis, 25 pathways, including the cell cycle, pathways in cancer, DNA replication, and focal adhesion, were significantly regulated by miR‐135a in RCC cells. Moreover, based on the results of this analysis, we investigated whether miR‐135a targeted the c‐MYC gene in RCC . Gain‐of‐function and luciferase reporter assays showed that c‐MYC was directly regulated by miR‐135a in RCC cells. Furthermore, c‐ MYC expression was significantly upregulated in RCC clinical specimens. Our data suggest that elucidation of tumor‐suppressive miR‐135a ‐mediated molecular pathways could reveal potential therapeutic targets in RCC .