TY - JOUR
T1 - The microRNAs miR-200b-3p and miR-429-5p target the LIMK1/CFL1 pathway to inhibit growth and motility of breast cancer cells
AU - Li, Dengfeng
AU - Wang, Hong
AU - Song, Hongming
AU - Xu, Hui
AU - Zhao, Bingkun
AU - Wu, Chenyang
AU - Hu, Jiashu
AU - Wu, Tianqi
AU - Xie, Dan
AU - Zhao, Junyong
AU - Shen, Qiang
AU - Fang, Lin
N1 - Funding Information:
from the National Natural Science Foundation of China and grant no.201640097 from the Shanghai Municipal Health Bureau of Shanghai, China (to L. Fang), Cancer Center Support Grant P30 CA016672 from the United States National Institutes of Health (to The University of Texas MD Anderson Cancer Center), startup funds from MD Anderson Cancer Center (to Q. Shen), and the Duncan Family Institute Seed Funding Research Program (to Q. Shen).
Publisher Copyright:
© Li et al.
PY - 2017/10/17
Y1 - 2017/10/17
N2 - 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.
AB - 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.
KW - Cell motility
KW - MiR-429-5p
KW - Proliferation
KW - Triple-negative breast cancer
KW - miR-200b-3p
UR - http://www.scopus.com/inward/record.url?scp=85031494214&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85031494214&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.19205
DO - 10.18632/oncotarget.19205
M3 - Article
C2 - 29156719
AN - SCOPUS:85031494214
SN - 1949-2553
VL - 8
SP - 85276
EP - 85289
JO - Oncotarget
JF - Oncotarget
IS - 49
ER -