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ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression.

Authors :
Ahn YH
Gibbons DL
Chakravarti D
Creighton CJ
Rizvi ZH
Adams HP
Pertsemlidis A
Gregory PA
Wright JA
Goodall GJ
Flores ER
Kurie JM
Source :
The Journal of clinical investigation [J Clin Invest] 2012 Sep; Vol. 122 (9), pp. 3170-83. Date of Electronic Publication: 2012 Aug 01.
Publication Year :
2012

Abstract

Metastatic cancer is extremely difficult to treat, and the presence of metastases greatly reduces a cancer patient's likelihood of long-term survival. The ZEB1 transcriptional repressor promotes metastasis through downregulation of microRNAs (miRs) that are strong inducers of epithelial differentiation and inhibitors of stem cell factors. Given that each miR can target multiple genes with diverse functions, we posited that the prometastatic network controlled by ZEB1 extends beyond these processes. We tested this hypothesis using a mouse model of human lung adenocarcinoma metastasis driven by ZEB1, human lung carcinoma cells, and human breast carcinoma cells. Transcriptional profiling studies revealed that ZEB1 controls the expression of numerous oncogenic and tumor-suppressive miRs, including miR-34a. Ectopic expression of miR-34a decreased tumor cell invasion and metastasis, inhibited the formation of promigratory cytoskeletal structures, suppressed activation of the RHO GTPase family, and regulated a gene expression signature enriched in cytoskeletal functions and predictive of outcome in human lung adenocarcinomas. We identified several miR-34a target genes, including Arhgap1, which encodes a RHO GTPase activating protein that was required for tumor cell invasion. These findings demonstrate that ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression and provide a compelling rationale to develop miR-34a as a therapeutic agent in lung cancer patients.

Details

Language :
English
ISSN :
1558-8238
Volume :
122
Issue :
9
Database :
MEDLINE
Journal :
The Journal of clinical investigation
Publication Type :
Academic Journal
Accession number :
22850877
Full Text :
https://doi.org/10.1172/JCI63608