CXCL12/CXCR4 promotes inflammation-driven colorectal cancer progression through activation of RhoA signaling by sponging miR-133a-3p

Journal of Experimental & Clinical Cancer Research

Xiaoxue Xu¹  Xiaohui Wang²  Shiyue Sun³  Xinfeng Yu³  Dong Wang³  Yuhang Zhang³  Rongrong Miao³  Xianjun Qu³  Shuqing Wang³ 

[1] Department of Central Laboratory, Capital Medical University;Department of General Surgery, Xuan Wu Hospital, Capital Medical University;Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University;

关键词: CXCR4;    RhoA;    miR-133a-3p;    lncRNA XIST;    CAC;   

DOI  :  10.1186/s13046-018-1014-x

来源: DOAJ

【 摘 要 】

Abstract Background Activation of CXCL12/CXCR4 axis has been found to be associated with invasion and metastasis in many cancers. However, the underlying mechanism remains elusive. Increasing data highlight that non-coding RNAs are linked to CRC progression. Methods The effects of CXCR4 were investigated using villin-CXCR4 transgenic mice model by flow cytometry assay, immunohistochemistry, and Western blot. The mechanism was explored through bioinformatics, luciferase reporter assay and RNA immunoprecipitation assay. Results We found that high CXCR4 expression exacerbated colitis-associated cancer in villin-CXCR4 transgenic mice. CXCR4 +/− Apc min/+ compound mutant mice demonstrated higher colorectal tumorigenesis than Apc min/+ mice. Furthermore, overexpression of CXCR4 was found to promote the epithelial-mesenchymal transition (EMT) and infiltration of myeloid-derived suppressor cells (MDSCs) and macrophages in colonic tissue, accelerating colitis-associated and Apc mutation-driven colorectal tumorigenesis and progression. Notably, miR-133a-3p was found to be significantly decreased in HCT116 cells overexpressing CXCR4 by miRNA sequencing. miR-133a-3p was proved to target RhoA, which is involved in cytoskeletal reorganization that drive cell motility. Importantly, CXCL12/CXCR4-induced upregulation of lncRNA XIST functioned as a ceRNA to sponge miR-133a-3p, thereby liberating the repression of RhoA by miR-133a-3p. The negative correlation of miR-133a-3p with RhoA was also confirmed in human CRC tissues and CXCR4 +/− mice. Conclusions Our findings revealed the critical role of CXCR4 in promoting progression of inflammatory colorectal cancer through recruiting immunocytes and enhancing cytoskeletal remodeling by lncRNA XIST/ miR-133a-3p/ RhoA signaling. These results provide novel potential therapeutic targets for hindering CXCL12/CXCR4-induced CRC progression.

【 授权许可】

Unknown