CXCL12/CXCR4 promotes inflammation-driven colorectal cancer progression through activation of RhoA signaling by sponging miR-133a-3p
CXCL12/CXCR4 promotes inflammation-driven colorectal cancer progression through activation of RhoA signaling by sponging miR-133a-3p
复制标题
CXCL12/CXCR4 通过 5 海绵 miR-133a-3p 激活 RhoA 信号传导，促进炎症驱动的结直肠癌进展 4
DOI：
10.1186/s13046-018-1014-x
复制
发表时间：
2019-01-24
影响因子：
11.3
通讯作者：
Qu, Xianjun
中科院分区：
文献类型：
--
作者：
Yu, Xinfeng;Wang, Dong;Qu, Xianjun
BackgroundActivation 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.MethodsThe 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.ResultsWe 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.ConclusionsOur 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.
