The microRNAs miR-200b-3p and miR-429-5p target the LIMK1/CFL1 pathway to inhibit growth and motility of breast cancer cells
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Dengfeng Li1,3, Hong Wang2,3, Hongming Song1, Hui Xu1, Bingkun Zhao1, Chenyang Wu1, Jiashu Hu1, Tianqi Wu1, Dan Xie1, Junyong Zhao1, Qiang Shen3 and Lin Fang1
1Department of Thyroid and Breast, Division of General Surgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China
2Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, People’s Republic of China
3Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Science, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, United States
Lin Fang, email: [email protected]
Qiang Shen, email: [email protected]
Keywords: miR-200b-3p, miR-429-5p, triple-negative breast cancer, proliferation, cell motility
Received: April 28, 2017 Accepted: June 28, 2017 Published: July 12, 2017
Triple-negative breast cancer (TNBC) has the worst prognosis of all subtypes of breast cancer (BC), with limited options for conventional therapy and no targeted therapies. MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression. In this study, we aimed to determine whether two members of the miR-200 family, miR-200b-3p and miR-429-5p, are involved in BC cell proliferation and motility and to elucidate their target genes and pathways. We performed a meta-analysis that reveals down-regulated expression of miR-200b-3p and miR-429-5p in BC tissues and cell lines, consistent with a lower expression of miR-200b-3p and miR-429-5p in MDA-MB-231 and HCC1937 cells than in MCF-7 and MCF-10 cells. Overexpression of miR-200b-3p and miR-429-5p significantly inhibited the proliferation, migration, and invasion of TNBC cells; suppressed the expression of markers for proliferation and metastasis in TNBC cells. We next demonstrated that LIM domain kinase 1 (LIMK1) is a direct target gene of miR-200b-3p and miR-429-5p. Inhibition of LIMK1 reduced the expression and phosphorylation of cofilin 1 (CFL1), which polymerizes and depolymerizes F-actin and G-actin to reorganize cellular actin cytoskeleton. In addition, transfection with mimics for miR-200b-3p and miR-429-5p arrested G2/M and G0/G1 cell cycles respectively, suppressed the expression of the cell cycle–related complexes, cyclin D1/CDK4/CDK6 and cyclin E1/CDK2, in TNBC cells. In conclusion, miR-200b-3p and miR-429-5p suppress proliferation, migration, and invasion in TNBC cells, via the LIMK1/CFL1 pathway. These results provide insight into how specific miRNAs regulate TNBC progression and suggest that the LIMK1/CFL1 pathway is a therapeutic target for treating TNBC.
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