Genome-wide screening identified that miR-134 acts as a metastasis suppressor by targeting integrin β1 in hepatocellular carcinoma

Ruopeng Zha; Weijie Guo; Zhenfeng Zhang; Zhaoping Qiu; Qifeng Wang; Jie Ding; Shenglin Huang; Taoyang Chen; Jianren Gu; Ming Yao; Xianghuo He

doi:10.1371/journal.pone.0087665

Genome-wide screening identified that miR-134 acts as a metastasis suppressor by targeting integrin β1 in hepatocellular carcinoma

PLoS One. 2014 Feb 3;9(2):e87665. doi: 10.1371/journal.pone.0087665. eCollection 2014.

Authors

Affiliations

¹ Shanghai Medical College, Fudan University, Shanghai, China ; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Shanghai Cancer Hospital, Fudan University, Shanghai, China.
⁴ Qi Dong Liver Cancer Institute, Qi Dong, Jiangsu, China.

Abstract

MicroRNAs (miRNAs) are small, single-stranded, non-coding RNAs that play pivotal roles in human cancer development and progression, such as tumor metastasis. Here, we identified the miRNAs that regulate hepatocellular carcinoma (HCC) cell migration by a high-throughput screening method using the classical wound-healing assay with time-lapse video microscopy and validation with a transwell migration assay. Eleven miRNAs (miR-134, -146b-3p, -188-3p, -525-3p, -661, -767-5p, -891a, -891b, -1244, -1247 and miR-1471) were found to promote or inhibit HCC cell migration. Further investigation revealed that miR-134 suppressed the invasion and metastasis of HCC cells in vitro and in vivo, and integrin beta 1 (ITGB1) was a direct and functional target gene of miR-134. Moreover, miR-134 inhibited the phosphorylation of focal adhesion kinase (FAK) and the activation of RhoA downstream of the ITGB1 pathway, thereby decreasing stress fiber formation and cell adhesion in HCC cells. In conclusion, we demonstrated that miR-134 is a novel metastasis suppressor in HCC and could be a potential therapeutic target for the treatment of HCC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Cell Adhesion / genetics
Cell Line, Tumor
Cell Movement / genetics*
Electrophoresis, Polyacrylamide Gel
Female
Focal Adhesion Protein-Tyrosine Kinases / genetics
Focal Adhesion Protein-Tyrosine Kinases / metabolism
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genome-Wide Association Study / methods*
Humans
Integrin beta1 / genetics*
Liver Neoplasms / genetics
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Male
MicroRNAs / genetics*
Microscopy, Confocal
Middle Aged
Neoplasm Metastasis
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / genetics
Stress Fibers / genetics
Stress Fibers / metabolism
Time-Lapse Imaging / methods
rhoA GTP-Binding Protein / genetics
rhoA GTP-Binding Protein / metabolism

Substances

Integrin beta1
MIRN134 microRNA, human
MicroRNAs
Focal Adhesion Protein-Tyrosine Kinases
rhoA GTP-Binding Protein

Grants and funding

This work was supported by grants from the National 973 Key Basic Research Program (2013CB910500); the National Natural Science Foundation of China (81125016, 81071637, and 91029728); The Key Specialized Project for the Infectious Diseases (2012ZX10002-009013); Shanghai Science and Technology Commission (11XD1404500); Shanghai Municipal Education Commission and Shanghai Municipal Health Bureau (11SG18, XBR2011039, and 20114Y159). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.