MicroRNA miR-142-3p regulates breast cancer cell invasiveness by synchronous targeting of integrin alpha V and multiple cytoskeletal elements

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Abstract

MicroRNAs (miRNAs, micro ribonucleic acids) are pivotal post-transcriptional regulators of gene expression. These endogenous small non-coding RNAs play significant roles in tumorigenesis and tumor progression. miR-142-3p expression is dysregulated in several breast cancer subtypes. We aimed at investigating the role of miR-142-3p in breast cancer cell invasiveness. Supported by transcriptomic Affymetrix array analysis and confirmatory investigations at the mRNA and protein level, we demonstrate that overexpression of miR-142-3p in MDA-MB-231, MDA-MB-468 and MCF-7 breast cancer cells leads to downregulation of Integrin-αV, RAC1, WASL (Wiskott-Aldrich syndrome-like, protein: N-WASP) and CFL2, molecules implicated in cytoskeletal regulation and cell motility. ROCK2, IL6ST, KLF4, PGRMC2 and ADCY9 were identified as additional targets in a subset of cell lines. Decreased matrigel invasiveness was associated with the miR-142-3p-induced expression changes. Confocal immunofluorescence microscopy, nanoscale atomic force microscopy and digital holographic microscopy revealed a restructuring of the intracellular actin cytoskeleton as well as a reduced cell volume and size. A more cortical actin distribution and a loss of membrane protrusions were observed in cells overexpressing miR-142-3p. Luciferase activation assays confirmed direct miR-142-3p-dependent regulation of the 3’ and WASL resulted in a significant reduction of cellular invasiveness, highlighting the contribution of these factors to the miRNA-dependent invasion phenotype. Our data identify ITGAV and several additional cytoskeleton-associated molecules as novel invasion-promoting targets of miR-142-3p in breast cancer. With its tumor suppressive potential, miR-142-3p is a promising candidate for future approaches of miRNA-based anti-metastatic cancer therapy.-untranslated region of ITGAV and WASL. siRNA-mediated depletion of ITGAV and WASL resulted in a significant reduction of cellular invasiveness, highlighting the contribution of these factors to the miRNA-dependent invasion phenotype. Our data identify ITGAV and several additional cytoskeleton-associated molecules as novel invasion-promoting targets of miR-142-3p in breast cancer. With its tumor suppressive potential, miR-142-3p is a promising candidate for future approaches of miRNA-based anti-metastatic cancer therapy.

Speakers from the University of Münster

Götte, Martin

Department of Gynecology and Obstetrics

Projects the talk is about

DAAD- Al Tawasul - Syndecan-1 and microRNA function in inflammatory breast cancer Duration: 01/01/2015 - 31/12/2015 Funded by: German Academic Exchange Service Type of project: Participation in other joint projects

Publications referred to in the talk

MicroRNA MIR-142-3p Inhibits Breast Cancer Cell Invasiveness by Synchronous Targeting of WASL, Integrin Alpha V, and Additional Cytoskeletal Elements Schwickert A., Weghake E., Brüggemann K., Engbers A., Brinkmann B., Kemper B., Seggewiß J., Stock C., Ebnet K., Kiesel L., Riethmüller C., Götte M. (2015) In: PloS one, 10(12). doi:10.1371/journal.pone.0143993 Research article (journal) | Peer reviewed | Published