miR‐515‐5p controls cancer cell migration through MARK 4 regulation

Abstract

© 2016 The Authors. Published under the terms of the CC BY 4.0 license. Here, we show that miR-515-5p inhibits cancer cell migration and metastasis. RNA-seq analyses of both oestrogen receptor receptor-positive and receptor-negative breast cancer cells overexpressing miR-515-5p reveal down-regulation of NRAS, FZD4, CDC42BPA, PIK3C2B and MARK4 mRNAs. We demonstrate that miR-515-5p inhibits MARK4 directly 3′ UTR interaction and that MARK4 knock-down mimics the effect of miR-515-5p on breast and lung cancer cell migration. MARK4 overexpression rescues the inhibitory effects of miR-515-5p, suggesting miR-515-5p mediates this process through MARK4 down-regulation. Furthermore, miR-515-5p expression is reduced in metastases compared to primary tumours derived from both in vivo xenografts and samples from patients with breast cancer. Conversely, miR-515-5p overexpression prevents tumour cell dissemination in a mouse metastatic model. Moreover, high miR-515-5p and low MARK4 expression correlate with increased breast and lung cancer patients' survival, respectively. Taken together, these data demonstrate the importance of miR-515-5p/MARK4 regulation in cell migration and metastasis across two common cancers. Synopsis miR-515-5p inhibits cancer progression, cell migration and metastasis through its direct target MARK4, a regulator of the cytoskeleton and cell motility. Moreover, reduced miR-515-5p and increased MARK4 levels in metastatic lung and breast cancer correlate with poor patient prognosis. MARK4 down-regulation promotes microtubule polymerisation. Increased cell spreading downstream of miR-515-5p overexpression or MARK4 silencing hinders cell motility and invasiveness. miR-515-5p overexpression or MARK4 silencing prevent organ colonisation by circulating tumour cells. MARK4 inhibitors may represent novel therapeutic agents to control cancer dissemination. miR-515-5p inhibits cancer progression, cell migration and metastasis through its direct target MARK4, a regulator of the cytoskeleton and cell motility. Moreover, reduced miR-515-5p and increased MARK4 levels in metastatic lung and breast cancer correlate with poor patient prognosis.