SOX2 regulates multiple malignant processes of breast cancer development through the SOX2/miR-181a-5p, miR-30e-5p/TUSC3 axis

Molecular Cancer

Research

Jianwen Que¹  Jian Zhu²  Qiong Hu³  Zhangwu Xiao⁴  Haikun Wang⁵  Qiaojia Huang⁶  Kuancan Liu⁷  Anding Gao⁸  Fuan Xie⁸  Baoshun Lin⁸  Rui Zhang⁹  Xiaopeng Lan⁹  Long Zhang^1,10  Weifeng Huang^1,11 

[1] Department of Medicine, Columbia University Medical Center, 10032, New York, NY, USA;Department of Microbiology and Immunology, University of Rochester, 14642, Rochester, NY, USA;Dong fang Hospital, Xiamen University, 350025, Fuzhou, Fujian, People’s Republic of China;Emergency Department of the 476 Hospital, Fuzhou General Hospital, PLA, 350002, Fuzhou, Fujian, People’s Republic of China;Institute Pasteur of Shanghai, Chinese Academy of Sciences, 200031, Shanghai, People’s Republic of China;Institute for Laboratory Medicine, Fuzhou General Hospital, PLA, 350025, Fuzhou, Fujian, People’s Republic of China;Institute for Laboratory Medicine, Fuzhou General Hospital, PLA, 350025, Fuzhou, Fujian, People’s Republic of China;Department of Medicine, Columbia University Medical Center, 10032, New York, NY, USA;Dong fang Hospital, Xiamen University, 350025, Fuzhou, Fujian, People’s Republic of China;Fuzhou General Hospital Clinical Medical School, Fujian Medical University, 350025, Fuzhou, People’s Republic of China;Institute for Laboratory Medicine, Fuzhou General Hospital, PLA, 350025, Fuzhou, Fujian, People’s Republic of China;Dong fang Hospital, Xiamen University, 350025, Fuzhou, Fujian, People’s Republic of China;Institute for Laboratory Medicine, Fuzhou General Hospital, PLA, 350025, Fuzhou, Fujian, People’s Republic of China;Fuzhou General Hospital Clinical Medical School, Fujian Medical University, 350025, Fuzhou, People’s Republic of China;Life Science Institute, Zhejiang University, 310058, Hangzhou, Zhejiang, People’s Republic of China;Medical College, China Three Gorges University, 443002, Yichang, Hubei, People’s Republic of China;

关键词: Sox2;    Breast cancer;    Tumourigenesis;    miRNA;   

DOI  :  10.1186/s12943-017-0632-9

 received in 2016-06-20, accepted in 2017-03-06,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundHigh levels of SOX2 protein are correlated with increased dissemination of breast cancer. However, the underlying molecular mechanisms are not fully understood.MethodsIn this study we investigate the role of SOX2 in breast cancer metastasis using multiple in vitro and in vivo assays including cell culture, shRNA-mediated knockdown, wound healing, colony formation, transwell chamber, xenograft and tail vein injection. Moreover, western blot, immunostaining, microarray and real-time PCR were used to determine the change of protein and miRNA levels. Luciferase assays were also used to evaluate activity which TUSC3 is a target of miR-181a-5p and miR-30e-5p, and the clinical survival relevance was analyzed by Kaplan-Meier analysis.ResultsWe identified a novel pathway involving SOX2 regulation of microRNAs to control the proliferation and migration of breast cancer cells. shRNA-mediated knockdown of SOX2 inhibits breast cancer cell expansion and migration. More importantly, we found that these changes are accompanied by significant reduction in the levels of two microRNAs, miR-181a-5p and miR-30e-5p. Overexpression of these two microRNAs leads to reduced protein levels of Tumor Suppressor Candidate 3 (TUSC3) in breast cancer cells; mutations of the potential binding sites in the 3’-UTR of TUSC3 abrogate the inhibitory effects of the microRNAs. We further found that upregulation of TUSC3 expression leads to reduced proliferation and migration of breast cancer cells. In human breast cancer samples the levels of TUSC3 protein are inversely correlated with those of SOX2 protein.ConclusionsTaken together, our work reveals a novel SOX2-mediated regulatory axis that plays critical roles in the proliferation, migration and invasiveness of breast cancer cells. Targeting this axis may provide beneficial effect in the treatment of breast cancer.

【 授权许可】

CC BY   
© The Author(s). 2017