The CCR2 3′UTR functions as a competing endogenous RNA to inhibit breast cancer metastasis

ABSTRACT Diverse RNA transcripts acting as competing endogenous RNAs (ceRNAs) can co-regulate each other9s expression by competing for shared microRNAs. CCR2 protein, the receptor for CCL2, is implicated in cancer progression. However, we found that a higher CCR2 mRNA level is remarkably associated with prolonged survival of breast cancer patients. These conflicting results prompted us to study the non-coding function of CCR2 mRNA. We found that the CCR2 3′ untranslated region (UTR) inhibited MDA-MB-231 and MCF-7 cell metastasis by repressing epithelial–mesenchymal transition (EMT) in vitro , and suppressed breast cancer metastasis in vivo . Mechanistically, the CCR2 3′UTR modulated the expression of the RhoGAP protein STARD13 via acting as a STARD13 ceRNA in a microRNA-dependent and protein coding-independent manner. The CCR2 3′UTR blocked the activation of RhoA–ROCK1 pathway, which is the downstream effector of STARD13, and thus decreased the phosphorylation level of myosin light chain 2 (MLC2) and formation of F-actin. Additionally, the function of the CCR2 3′UTR was dependent on STARD13 expression. In conclusion, our results confirmed that the CCR2 3′UTR acts as a metastasis suppressor by acting as a ceRNA for STARD13 and thus inhibiting RhoA–ROCK1–MLC–F-actin pathway in breast cancer cells. This article has an associated First Person interview with the first author of the paper.