Cargando…

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 tyros...

Descripción completa

Detalles Bibliográficos
Autores principales: Lian, Sen, Park, Jung Sun, Xia, Yong, Nguyen, Thi Thinh, Joo, Young Eun, Kim, Kyung Keun, Kim, Hark Kyun, Jung, Young Do
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085666/
https://www.ncbi.nlm.nih.gov/pubmed/27689991
http://dx.doi.org/10.3390/ijms17101633
_version_ 1782463616183697408
author Lian, Sen
Park, Jung Sun
Xia, Yong
Nguyen, Thi Thinh
Joo, Young Eun
Kim, Kyung Keun
Kim, Hark Kyun
Jung, Young Do
author_facet Lian, Sen
Park, Jung Sun
Xia, Yong
Nguyen, Thi Thinh
Joo, Young Eun
Kim, Kyung Keun
Kim, Hark Kyun
Jung, Young Do
author_sort Lian, Sen
collection PubMed
description 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 of miR-375 and RON expression in gastric cancer metastasis has not been sufficiently studied. In silico analysis identified miR-375 binding sites in the 3′-untranslated regions (3′-UTR) of the RON-encoding gene. Expression of miR-375 resulted in reduced activity of a luciferase reporter containing the 3′-UTR fragments of RON-encoding mRNA, confirming that miR-375 directly targets the 3′-UTR of RON mRNA. Moreover, we found that overexpression of miR-375 inhibited 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. Ectopic miR-375 expression 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 to miR-375 overexpression, 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 that miR-375 acts as a suppressor of metastasis in gastric cancer by targeting RON, and might represent a new potential therapeutic target for gastric cancer.
format Online
Article
Text
id pubmed-5085666
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-50856662016-11-01 MicroRNA-375 Functions as a Tumor-Suppressor Gene in Gastric Cancer by Targeting Recepteur d’Origine Nantais Lian, Sen Park, Jung Sun Xia, Yong Nguyen, Thi Thinh Joo, Young Eun Kim, Kyung Keun Kim, Hark Kyun Jung, Young Do Int J Mol Sci Article 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 of miR-375 and RON expression in gastric cancer metastasis has not been sufficiently studied. In silico analysis identified miR-375 binding sites in the 3′-untranslated regions (3′-UTR) of the RON-encoding gene. Expression of miR-375 resulted in reduced activity of a luciferase reporter containing the 3′-UTR fragments of RON-encoding mRNA, confirming that miR-375 directly targets the 3′-UTR of RON mRNA. Moreover, we found that overexpression of miR-375 inhibited 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. Ectopic miR-375 expression 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 to miR-375 overexpression, 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 that miR-375 acts as a suppressor of metastasis in gastric cancer by targeting RON, and might represent a new potential therapeutic target for gastric cancer. MDPI 2016-09-27 /pmc/articles/PMC5085666/ /pubmed/27689991 http://dx.doi.org/10.3390/ijms17101633 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lian, Sen
Park, Jung Sun
Xia, Yong
Nguyen, Thi Thinh
Joo, Young Eun
Kim, Kyung Keun
Kim, Hark Kyun
Jung, Young Do
MicroRNA-375 Functions as a Tumor-Suppressor Gene in Gastric Cancer by Targeting Recepteur d’Origine Nantais
title MicroRNA-375 Functions as a Tumor-Suppressor Gene in Gastric Cancer by Targeting Recepteur d’Origine Nantais
title_full MicroRNA-375 Functions as a Tumor-Suppressor Gene in Gastric Cancer by Targeting Recepteur d’Origine Nantais
title_fullStr MicroRNA-375 Functions as a Tumor-Suppressor Gene in Gastric Cancer by Targeting Recepteur d’Origine Nantais
title_full_unstemmed MicroRNA-375 Functions as a Tumor-Suppressor Gene in Gastric Cancer by Targeting Recepteur d’Origine Nantais
title_short MicroRNA-375 Functions as a Tumor-Suppressor Gene in Gastric Cancer by Targeting Recepteur d’Origine Nantais
title_sort microrna-375 functions as a tumor-suppressor gene in gastric cancer by targeting recepteur d’origine nantais
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085666/
https://www.ncbi.nlm.nih.gov/pubmed/27689991
http://dx.doi.org/10.3390/ijms17101633
work_keys_str_mv AT liansen microrna375functionsasatumorsuppressorgeneingastriccancerbytargetingrecepteurdoriginenantais
AT parkjungsun microrna375functionsasatumorsuppressorgeneingastriccancerbytargetingrecepteurdoriginenantais
AT xiayong microrna375functionsasatumorsuppressorgeneingastriccancerbytargetingrecepteurdoriginenantais
AT nguyenthithinh microrna375functionsasatumorsuppressorgeneingastriccancerbytargetingrecepteurdoriginenantais
AT jooyoungeun microrna375functionsasatumorsuppressorgeneingastriccancerbytargetingrecepteurdoriginenantais
AT kimkyungkeun microrna375functionsasatumorsuppressorgeneingastriccancerbytargetingrecepteurdoriginenantais
AT kimharkkyun microrna375functionsasatumorsuppressorgeneingastriccancerbytargetingrecepteurdoriginenantais
AT jungyoungdo microrna375functionsasatumorsuppressorgeneingastriccancerbytargetingrecepteurdoriginenantais