miR-143 and miR-145 synergistically regulate ERBB3 to suppress cell proliferation and invasion in breast cancer

Molecular Cancer

Research

Rui Liu¹  Jialu Li¹  Yi Ba¹  Ting Deng¹  Xiujuan Gao¹  Xin Yan²  Weixu Chen³  Hongwei Liang⁴  Xueliang Wang⁴  Suyang Zhang⁴  Xi Chen⁴  Chen-Yu Zhang⁴  Yanqing Liu⁴  Chihao Zhao⁴  Nan Wang⁴  Minghui Liu⁴  Ke Zen⁴  Baorui Liu⁵ 

[1] Department of Gastrointestinal Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Huanhuxi Road, 300060, Tiyuanbei, Tianjin, China;Department of Gastrointestinal Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Huanhuxi Road, 300060, Tiyuanbei, Tianjin, China;Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, 210093, Nanjing, China;The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, 210008, Nanjing, Jiangsu, P.R, China;First Affiliated Hospital of Nanjing Medical University, 210009, Nanjing, China;Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, 210093, Nanjing, China;The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, 210008, Nanjing, Jiangsu, P.R, China;

关键词: microRNA;    miR-143;    miR-145;    ERBB3;    Breast cancer;    Proliferation;    Invasion;   

DOI  :  10.1186/1476-4598-13-220

 received in 2014-05-17, accepted in 2014-09-15,  发布年份 2014

来源: Springer

【 摘 要 】

IntroductionERBB3, one of the four members of the ErbB family of receptor tyrosine kinases, plays an important role in breast cancer etiology and progression. In the present study, we aimed to identify novel miRNAs that can potentially target ERBB3 and their biological functions.MethodThe expression levels of miR-143/145 and target mRNA were examined by relative quantification RT-PCR, and the expression levels of target protein were detected by Western blot. We used bioinformatic analyses to search for miRNAs that can potentially target ERBB3. Luciferase reporter plasmids were constructed to confirm direct targeting. Furthermore, the biological consequences of the targeting of ERBB3 by miR-143/145 were examined by cell proliferation and invasion assays in vitro and by the mouse xenograft tumor model in vivo.ResultsWe identified an inverse correlation between miR-143/145 levels and ERBB3 protein levels, but not between miR-143/145 levels and ERBB3 mRNA levels, in breast cancer tissue samples. We identified specific targeting sites for miR-143 and miR-145 (miR-143/145) in the 3’-untranslated region (3’-UTR) of the ERBB3 gene and regulate ERBB3 expression. We demonstrated that the repression of ERBB3 by miR-143/145 suppressed the proliferation and invasion of breast cancer cells, and that miR-143/145 showed an anti-tumor effect by negatively regulating ERBB3 in the xenograft mouse model. Interestingly, miR-143 and miR-145 showed a cooperative repression of ERBB3 expression and cell proliferation and invasion in breast cancer cells, such that the effects of the two miRNAs were greater than with either miR-143 or miR-145 alone.ConclusionTaken together, our findings provide the first clues regarding the role of the miR-143/145 cluster as a tumor suppressor in breast cancer through the inhibition of ERBB3 translation. These results also support the idea that different miRNAs in a cluster can synergistically repress a given target mRNA.

【 授权许可】

Unknown   
© Yan et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.