MicroRNA-146a Suppresses Metastatic Activity in Brain Metastasis

Abstract

Primary lung tumors, breast tumors, and melanoma metastasize mainly in the brain where therapy is limited to surgery and radiation. To investigate the molecular basis of brain metastases, we isolated brain-trophic metastatic MDA-MB-435-LvBr2 (LvBr2) cells via left ventricle (LV) injection of MDA-MB-435 cells into immunodeficiency (NOD/ SCID) mice. Whereas parent MDA-MB-435 cells displayed an elongated morphology, LvBr2 cells were round and displayed an aggregated distribution. LvBr2 cells expressed lower β-catenin levels and higher heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC) levels than parental cells. Since microRNAs are known to play an important role in cancer progression including metastasis, we screened microRNAs expressed specifically in brain metastases. MicroRNA-146a was almost undetectable in LvBr2 cells and highly expressed in the parental cells. Overexpression of miR-146a increased β-catenin expression and suppressed the migratory and invasive activity of LvBr2 cells. The miR-146a-elicited decrease in hnRNPC in turn lowered the expression of MMP-1, uPA, and uPAR and inhibited the migratory and invasive activity of LvBr2 cells. Taken together, our findings indicate that miR-146a is virtually absent from brain metastases and can suppress their metastatic potential including their migratory and invasive activities associated with upregulation of β-catenin and downregulation of hnRNPC.

Serum Levels of miR-19b and miR-146a as Prognostic Biomarkers for Non-Small Cell Lung Cancer

“…Both the tissue and serum levels of miR-19b were increased as TNM stage increased, indicating the important function of miR-19b in the occurrence, progression, and metastasis of NSCLC. Several studies reported that the upregulation of miR-146a inhibits cancer metastasis (Kogo et al 2011;Hwang et al 2012;Chen et al 2013a). Rong et al (2014) found that low expression of miR-146a was associated with TNM and LNM in patients with hepatocellular carcinoma.…”

Advances in decoding breast cancer brain metastasis

“…In another study comparing breast cancer patients with or without brain metastasis, up-regulation of microRNA-10b was identified to be strongly associated with the development of brain metastasis [56]. Several microRNAs were able to suppress brain metastasis in breast cancer cells: 1) microRNA-7 down-regulates KLF4 in the cancer stem-like cell (CSC) population of MDA-MB-231 brain-seeking cells [57]; 2) microRNA-146a targets beta-catenin and hnRNPC in the MDA-MB-435 experimental brain metastasis model [58]; 3) microRNA-1258 targets heparanase to suppress brain metastasis in the MDA-MB-231 experimental brain metastasis model [59]. In contrast, miR-141 was shown to promote brain metastasis in several breast cancer cell lines [22].…”

MicroRNAs in the Regulation of MMPs and Metastasis

“…This was, however, an indirect effect purported to be mediated via the heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC) [93]. …”