TY - JOUR
T1 - MALAT1 rs664589 Polymorphism Inhibits Binding to miR-194-5p, Contributing to Colorectal Cancer Risk, Growth, and Metastasis
AU - Wu, Shenshen
AU - Sun, Hao
AU - Wang, Yajie
AU - Yang, Xi
AU - Meng, Qingtao
AU - Yang, Hongbao
AU - Zhu, Haitao
AU - Tang, Weiyan
AU - Li, Xiaobo
AU - Aschner, Michael
AU - Chen, Rui
N1 - Funding Information:
This work was financially supported by National Natural Science Foundation of China (81472938, 81861138017, and 91643109 to R. Chen), the Thousand Young Talents Plan of China (to R. Chen), the Fund of the Distinguished Talents of Jiangsu Province (BK20150021 to R. Chen), the Fund of the Distinguished Professor of Jiangsu Province (to R. Chen), the Natural Science Foundation of Jiangsu Province (BK20151418 to X. Li), the Six Talent Peaks Project in Jiangsu Province (2016-WSN-002 to R. Chen), the Open Research Fund of the State Key Laboratory of Bioelectronics, Southeast University to R. Chen, the Fundamental Research Funds for the Central Universities (to R. Chen, X. Li, and S. Wu), the Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX17_0187 to S. Wu,), the National Institute of Environmental Health Sciences (NIEHS; R01 ES10563, R01 ES07331, and R01 ES020852 to M. Aschner).
Funding Information:
This work was financially supported by National Natural Science Foundation of China (81472938, 81861138017, and 91643109 to R. Chen), the Thousand Young Talents Plan of China (to R. Chen), the Fund of the Distinguished Talents of Jiangsu Province (BK20150021 to R. Chen), the Fund of the Distinguished Professor of Jiangsu Province (to R. Chen), the Natural Science Foundation of Jiangsu Province (BK20151418 to X. Li), the Six Talent Peaks Project in Jiangsu Province (2016-WSN-002 to R. Chen), the Open Research Fund of the State Key Laboratory of Bioelectronics, Southeast University to R. Chen, the Fundamental
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/10/15
Y1 - 2019/10/15
N2 - Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) is an evolutionarily highly conserved lncRNA that contributes to colorectal cancer development. However, the exact molecular mechanisms connecting MALAT1 to colorectal cancer have not been fully elucidated. Here, we performed a case-control study in 1,078 patients with colorectal cancer and 1,175 healthy controls to evaluate the association between potentially functional genetic variants of MALAT1 and survival outcomes in patients with colorectal cancer. MALAT1 rs664589 CG/GG genotypes significantly increased the associated risk and decreased overall survival of patients with colorectal cancer compared with the CC genotype. In vitro and in vivo experiments showed that the rs664589 C to G mutation facilitated carcinogenesis and metastasis of colorectal cancer. Mechanistically, the miRNA miR-194-5p targeted MALAT1 for degradation in the nucleus in an Ago2-dependent manner; the rs664589 G allele altered the binding of MALAT1 to miR-194-5p, resulting in increased expression of MALAT1. Colorectal cancer cells and human tissues with the rs664589 CG/GG genotype expressed significantly higher MALAT1 than those with the rs664589 CC genotype. Multivariate Cox regression analysis showed that MALAT1 was a poor prognostic factor of colorectal cancer. In summary, MALAT1 with the rs664589 G allele demonstrates altered binding to miR-194-5p in the nucleus, leading to increased MALAT1 expression and enhanced colorectal cancer development. Significance: These findings highlight the functional role of MALAT1 polymorphism in colorectal cancer metastasis and survival as well as the underlying mechanism.
AB - Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) is an evolutionarily highly conserved lncRNA that contributes to colorectal cancer development. However, the exact molecular mechanisms connecting MALAT1 to colorectal cancer have not been fully elucidated. Here, we performed a case-control study in 1,078 patients with colorectal cancer and 1,175 healthy controls to evaluate the association between potentially functional genetic variants of MALAT1 and survival outcomes in patients with colorectal cancer. MALAT1 rs664589 CG/GG genotypes significantly increased the associated risk and decreased overall survival of patients with colorectal cancer compared with the CC genotype. In vitro and in vivo experiments showed that the rs664589 C to G mutation facilitated carcinogenesis and metastasis of colorectal cancer. Mechanistically, the miRNA miR-194-5p targeted MALAT1 for degradation in the nucleus in an Ago2-dependent manner; the rs664589 G allele altered the binding of MALAT1 to miR-194-5p, resulting in increased expression of MALAT1. Colorectal cancer cells and human tissues with the rs664589 CG/GG genotype expressed significantly higher MALAT1 than those with the rs664589 CC genotype. Multivariate Cox regression analysis showed that MALAT1 was a poor prognostic factor of colorectal cancer. In summary, MALAT1 with the rs664589 G allele demonstrates altered binding to miR-194-5p in the nucleus, leading to increased MALAT1 expression and enhanced colorectal cancer development. Significance: These findings highlight the functional role of MALAT1 polymorphism in colorectal cancer metastasis and survival as well as the underlying mechanism.
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UR - http://www.scopus.com/inward/citedby.url?scp=85073310259&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-19-0773
DO - 10.1158/0008-5472.CAN-19-0773
M3 - Article
C2 - 31311811
AN - SCOPUS:85073310259
VL - 79
SP - 5432
EP - 5441
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 20
ER -