MicroRNA-375 Functions as a Tumor-Suppressor Gene in Gastric Cancer by Targeting Recepteur d'Origine Nantais.
Emerging evidence supports a fundamental role for microRNAs (miRNA) in regulating cancer metastasis. Recently,microRNA-375(miR-375) was reported to be downregulated in many types of cancers, including gastric cancer. Increase in the expression of Recepteur d'Origine Nantais (RON), a receptor tyrosine kinase, has been reported in tumors. However, the function ofmiR-375and RON expression in gastric cancer metastasis has not been sufficiently studied. In silico analysis identifiedmiR-375binding sites in the 3'-untranslated regions (3'-UTR) of the RON-encoding gene. Expression ofmiR-375resulted in reduced activity of a luciferase reporter containing the 3'-UTR fragments of RON-encoding mRNA, confirming thatmiR-375directly targets the 3'-UTR of RON mRNA. Moreover, we found that overexpression ofmiR-375inhibited mRNA and protein expression of RON, which was accompanied by the suppression of cell proliferation, migration, and invasion in gastric cancer AGS and MKN-28 cells. EctopicmiR-375expression also induced G1 cell cycle arrest through a decrease in the expression of cyclin D1, cyclin D3, and in the phosphorylation of retinoblastoma (Rb). Knockdown of RON by RNAi, similar tomiR-375overexpression, suppressed tumorigenic properties and induced G1 arrest through a decrease in the expression of cyclin D1, cyclin D3, and in the phosphorylation of Rb. Thus, our study provides evidence thatmiR-375acts as a suppressor of metastasis in gastric cancer by targeting RON, and might represent a new potential therapeutic target for gastric cancer.
Research Institute of Medical Sciences, Chonnam National University Medical School, 501-190 Gwangju, Korea. senlian9@gmail.com.
Sen
S
Lian
Research Institute of Medical Sciences, Chonnam National University Medical School, 501-190 Gwangju, Korea. gene-pjs@hanmail.net.
Jung Sun
JS
Park
Research Institute of Medical Sciences, Chonnam National University Medical School, 501-190 Gwangju, Korea. xiayong0728@126.com.
Yong
Y
Xia
Research Institute of Medical Sciences, Chonnam National University Medical School, 501-190 Gwangju, Korea. thinhnt1984@gmail.com.
Thi Thinh
TT
Nguyen
Research Institute of Medical Sciences, Chonnam National University Medical School, 501-190 Gwangju, Korea. yejoo@chonnam.ac.kr.
Young Eun
YE
Joo
Research Institute of Medical Sciences, Chonnam National University Medical School, 501-190 Gwangju, Korea. kimkk@chonnam.ac.kr.
Kyung Keun
KK
Kim
Biomolecular Function Research Branch Division of Precision Medicine and Cancer Informatics, Division of Precision Medicine and Cancer Informatics, National Cancer Center, 410-769 Goyang, Korea. hkim@ncc.re.kr.
Hark Kyun
HK
Kim
Research Institute of Medical Sciences, Chonnam National University Medical School, 501-190 Gwangju, Korea. ydjung@chonnam.ac.kr.|Department of Biochemistry, Chonnam National University Medical School, 5 Hakdong, 501-190 Gwangju, Korea. ydjung@chonnam.ac.kr.
Young Do
YD
Jung
Recepteur d’Origine Nantais; gastric cancer; microRNA-375
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