TY - JOUR
T1 - MIR-515-5p controls cancer cell migration through MARK4 regulation
AU - Pardo, Olivier E.
AU - Castellano, Leandro
AU - Munro, Catriona E.
AU - Hu, Yili
AU - Mauri, Francesco
AU - Krell, Jonathan
AU - Lara, Romain
AU - Pinho, Filipa G.
AU - Choudhury, Thameenah
AU - Frampton, Adam E.
AU - Pellegrino, Loredana
AU - Pshezhetskiy, Dmitry
AU - Wang, Yulan
AU - Waxman, Jonathan
AU - Seckl, Michael J.
AU - Stebbing, Justin
N1 - Publisher Copyright:
© 2016 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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.
AB - 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.
KW - breast cancer
KW - lung cancer
KW - microRNAs
KW - microtubule affinity-regulating kinase 4
KW - MIR-515-5p
UR - http://www.scopus.com/inward/record.url?scp=84963553307&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84963553307&partnerID=8YFLogxK
U2 - 10.15252/embr.201540970
DO - 10.15252/embr.201540970
M3 - Article
C2 - 26882547
AN - SCOPUS:84963553307
SN - 1469-221X
VL - 17
SP - 570
EP - 584
JO - EMBO Reports
JF - EMBO Reports
IS - 4
ER -
