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

Abstract

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+/−Apcmin/+ compound mutant mice demonstrated higher colorectal tumorigenesis than Apcmin/+ 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.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-1014-x) contains supplementary material, which is available to authorized users.

Overexpression of Mitochondrial IF1 Prevents Metastatic Disease of Colorectal Cancer by Enhancing Anoikis and Tumor Infiltration of NK Cells

“…In addition, shIF1 cells could diminish immune surveillance of NK cells by generating soluble activating receptor ligands, such as cFLIP to block induction of apoptosis by TNF-α, Fas-L/Fas and TRAIL receptors [47]. Interestingly, shIF1 cells reveal significant increased expression of the CXC chemokine receptor 4 (CXCR4), which is involved in the inhibition of the activation and proliferation of NK cells by tumor cells [48,49] (Figure 7E). Moreover, shIF1 cells significantly increased the expression of the transcription factor SMAD3 and of the ecto-5'nucleotidase CD73/NT5E, which is under the control of SMAD3, an enzyme that generates adenosine in the tumor microenvironment leading to the suppression of multiple immune subsets including NK cells [50,51] ( Figure 7E).…”

Inflammatory Responses during Tumour Initiation: From Zebrafish Transgenic Models of Cancer to Evidence from Mouse and Man

“…However, the pro-tumour effect of Cxcr4 signalling at the preneoplastic stage was macrophage specific [142]. In the mouse APC min model of colorectal cancer, Cxcr4 −/− mice exhibited reduced macrophage infiltration and polyp formation [182]. Furthermore, in the mouse Lewis lung carcinoma model, inhibition of Cxcr4 greatly reduced tumour-associated inflammation and tumour growth [183].…”

“…Thus, there is some evidence that Cxcr4 signalling recruits macrophages and has a pro-tumour effect during early stage tumourigenesis in mammalian models. Cxcr4 has also been implicated in the recruitment of neutrophils and G-MDSCs to cancer cells in mouse xenograft models, resulting in tumour-promoting effects [182,[184][185][186].…”

Differential RNA editing between epithelial and mesenchymal tumors impacts mRNA abundance in immune response pathways

“…1B). Notable differentially edited genes include RHOA, which is active in cell migration and is associated with metastasis in multiple cancer types [42][43][44] , and ARL16, a reported negative regulator of RIG-I activity 45 , consistent with the observed enrichment of immune-relevant genes that were differentially edited in bulk tumors. Overall, the findings from single cell data support the hypothesis that editing differences between bulk E and M tumors mainly reflect changes occurring in cancer cells.…”