title: WAVE3, an actin remodeling protein, is regulated by the metastasis suppressor microRNA, miR-31, during the invasion-metastasis cascade.
abstract: WAVE3, an actin cytoskeleton remodeling protein, is highly expressed in advanced stages of breast cancer and influences tumor cell invasion. Loss of miR-31 has been associated with cancer progression and metastasis. Here, we show that the activity of WAVE3 to promote cancer cell invasion is regulated by miR-31. An inverse correlation was demonstrated between expression levels of WAVE3 and miR-31 in invasive versus noninvasive breast cancer cell lines. miR-31 directly targeted the 3'-UTR of the WAVE3 mRNA and inhibited its expression in the invasive cancer cells, i.e., miR-31-mediated down-regulation of WAVE3 resulted in a significant reduction in the invasive phenotype of cancer cells. This relationship was specific to the loss of WAVE3 expression because re-expression of a miR-31-resistant form of WAVE3 reversed miR-31-mediated inhibition of cancer cell invasion. Furthermore, expression of miR-31 correlates inversely with breast cancer progression in humans, where an increase in expression of miR-31 target genes was observed as the tumors progressed to more aggressive forms. In conclusion, a novel mechanism for the regulation of WAVE3 expression in cancer cells has been identified, which controls the invasive properties of cancer cells. The study also identifies a critical role for WAVE3, downstream of miR-31, in the invasion-metastasis cascade.
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. sosseyk@ccf.org
authors.forename: Khalid
authors.initials: K
authors.lastname: Sossey-Alaoui
authors.forename: Erinn
authors.initials: E
authors.lastname: Downs-Kelly
authors.forename: Mitali
authors.initials: M
authors.lastname: Das
authors.forename: Lahoucine
authors.initials: L
authors.lastname: Izem
authors.forename: Raymond
authors.initials: R
authors.lastname: Tubbs
authors.forename: Edward F
authors.initials: EF
authors.lastname: Plow
mesh_terms: D020413:3' Untranslated Regions; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000517:prevention & control; D015854:Up-Regulation; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C533896:MIRN200 microRNA, human; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; C120153:WASF3 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family