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 other's 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.

• Authors: Jinhang Hu, Xiaoman Li, Xinwei Guo, Qianqian Guo, Chenxi Xiang, Zhiting Zhang, Yingying Xing, Tao Xi, Lufeng Zheng
• Journal: Journal of cell science (J Cell Sci) Vol. 130 Issue 19 Pg. 3399-3413 (Oct 01 2017) ISSN: 1477-9137 [Electronic] England
• PMID: 28818997 (Publication Type: Journal Article)
• Copyright: © 2017. Published by The Company of Biologists Ltd.

Chemical References

• 3' Untranslated Regions
• CCR2 protein, human
• GTPase-Activating Proteins
• RNA, Neoplasm
• Receptors, CCR2
• STARD13 protein, human
• Tumor Suppressor Proteins
• rho GTPase-activating protein
• RHOA protein, human
• ROCK1 protein, human
• rho-Associated Kinases
• rhoA GTP-Binding Protein

Topics

• 3' Untranslated Regions
• Breast Neoplasms (genetics, metabolism, pathology)
• Female
• GTPase-Activating Proteins (genetics, metabolism)
• Humans
• MCF-7 Cells
• Neoplasm Metastasis
• RNA, Neoplasm (genetics, metabolism)
• Receptors, CCR2 (genetics, metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)
• rho-Associated Kinases (genetics, metabolism)
• rhoA GTP-Binding Protein (genetics, metabolism)