title: ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression.
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.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Ahn
authors.forename: Don L
authors.initials: DL
authors.lastname: Gibbons
authors.forename: Deepavali
authors.initials: D
authors.lastname: Chakravarti
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Zain H
authors.initials: ZH
authors.lastname: Rizvi
authors.forename: Henry P
authors.initials: HP
authors.lastname: Adams
authors.forename: Alexander
authors.initials: A
authors.lastname: Pertsemlidis
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gregory
authors.forename: Josephine A
authors.initials: JA
authors.lastname: Wright
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Goodall
authors.forename: Elsa R
authors.initials: ER
authors.lastname: Flores
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kurie
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000230:Adenocarcinoma / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002469:Cell Separation; D002478:Cells, Cultured; D015536:Down-Regulation; D004318:Doxycycline / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D018398:Homeodomain Proteins; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D051379:Mice; D057507:Mice, 129 Strain; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C115051:TP63 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D008156:Luciferases; D020741:rho GTP-Binding Proteins; D004318:Doxycycline