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PMID: 22850877 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

The Journal of clinical investigation ·Vol. 122 ·No. 9 ·2012-09-00 ·Pages 3170-83

Ahn YH, Gibbons DL, Chakravarti D, Creighton CJ, Rizvi ZH, Adams HP, Pertsemlidis A, Gregory PA, Wright JA, Goodall GJ, Flores ER, Kurie JM

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.

MeSH Terms
Actin Cytoskeleton/metabolism Adenocarcinoma/metabolism,mortality,secondary Animals Cell Line, Tumor Cell Movement Cell Proliferation Cell Separation Cells, Cultured Down-Regulation Doxycycline/pharmacology Epithelial-Mesenchymal Transition Gene Expression Regulation, Neoplastic Genes, Reporter Homeodomain Proteins Humans Luciferases/biosynthesis,genetics Lung Neoplasms/metabolism,mortality,pathology Mice Mice, 129 Strain MicroRNAs/genetics,metabolism Neoplasm Transplantation Oligonucleotide Array Sequence Analysis Promoter Regions, Genetic Signal Transduction Statistics, Nonparametric Transcription Factors/metabolism Transcriptome Transforming Growth Factor beta/pharmacology,physiology Tumor Suppressor Proteins/metabolism Zinc Finger E-box-Binding Homeobox 1 rho GTP-Binding Proteins/metabolism
Chemicals
Homeodomain Proteins MIRN34 microRNA, human MicroRNAs TP63 protein, human Transcription Factors Transforming Growth Factor beta Tumor Suppressor Proteins ZEB1 protein, human Zinc Finger E-box-Binding Homeobox 1 Luciferases rho GTP-Binding Proteins Doxycycline
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Ahn Young-Ho
Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Gibbons Don L
Chakravarti Deepavali
Creighton Chad J
Rizvi Zain H
Adams Henry P
Pertsemlidis Alexander
Gregory Philip A
Wright Josephine A
Goodall Gregory J
Flores Elsa R
Kurie Jonathan M
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI63608
Published
2012-09-00
Epub
2012-00-01
Pages
3170-83
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC3428095
Subset
IM
Grants
NCI NIH HHS · R01 CA160394 · United States
NCI NIH HHS · R01CA134796 · United States
NCI NIH HHS · P50 CA70907 · United States
Howard Hughes Medical Institute · United States
Medical Research Council · United Kingdom
NCI NIH HHS · R01 CA134796 · United States
NCI NIH HHS · R01 CA157450 · United States
NCI NIH HHS · R01 CA129632 · United States
NCI NIH HHS · P30 CA125123 · United States
NCI NIH HHS · P50 CA070907 · United States
NCI NIH HHS · K08 CA151651 · United States
Databases
GEO
GSE38341
External Links
PubMed source DOI: 10.1172/JCI63608 PMC Full Text View journal details
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