Exosomal miR-146a-5p and miR-155-5p promote CXCL12/CXCR7-induced metastasis of colorectal cancer by crosstalk with cancer-associated fibroblasts

Abstract

C-X-C motif chemokine receptor 7 (CXCR7) is a newly discovered atypical chemokine receptor that binds to C-X-C motif chemokine ligand 12 (CXCL12) with higher affinity than CXCR4 and is associated with the metastasis of colorectal cancer (CRC). Cancer-associated fibroblasts (CAFs) have been known to promote tumor progression. However, whether CAFs are involved in CXCR7-mediated metastasis of CRC remains elusive. We found a significant positive correlation between CXCR7 expression and CAF activation markers in colonic tissues from clinical specimens and in villin-CXCR7 transgenic mice. RNA sequencing revealed a coordinated increase in the levels of miR-146a-5p and miR-155-5p in CXCR7-overexpressing CRC cells and their exosomes. Importantly, these CRC cell-derived miR-146a-5p and miR-155-5p could be uptaken by CAFs via exosomes and promote the activation of CAFs through JAK2–STAT3/NF-κB signaling by targeting suppressor of cytokine signaling 1 (SOCS1) and zinc finger and BTB domain containing 2 (ZBTB2). Reciprocally, activated CAFs further potently enhanced the invasive capacity of CRC cells. Mechanistically, CAFs transfected with miR-146a-5p and miR-155-5p exhibited a robust increase in the levels of inflammatory cytokines interleukin-6, tumor necrosis factor-α, transforming growth factor-β, and CXCL12, which trigger the epithelial–mesenchymal transition and pro-metastatic switch of CRC cells. More importantly, the activation of CAFs by miR-146a-5p and miR-155-5p facilitated tumor formation and lung metastasis of CRC in vivo using tumor xenograft models. Our work provides novel insights into CXCR7-mediated CRC metastasis from tumor–stroma interaction and serum exosomal miR-146a-5p and miR-155-5p could serve as potential biomarkers and therapeutic targets for inhibiting CRC metastasis.

Potential Application of Leelamine as a Novel Regulator of Chemokine-Induced Epithelial-to-Mesenchymal Transition in Breast Cancer Cells

“…The results show a substantial decrease in mesenchymal markers along with a decrease in MnSOD level, and conversely, by observing increase in the levels of epithelial markers, it was demonstrated that LEE could regulate both cellular invasion and migration through modulating MnSOD and the EMT process. Thereafter, to confirm the association between CXCR7/4 and the EMT process, we checked the protein expression level under CXCL12 stimulation [ 47 , 48 ]. It was confirmed that treatment with CXCL12 increased the expression of MnSOD along with an increase in CXCR7/4.…”

“…The EMT process is mediated through various transcription factors, inflammatory cytokines, growth factors, and other proteins and enzymes [ 44 ]. It has been also reported that CXCL12 can induce the EMT process through modulating the CXCR4/7 axis to promote cellular invasion and migration [ 47 , 48 ].…”

The Underlying Roles of Exosome-Associated PIGR in Fatty Acid Metabolism and Immune Signaling in Colorectal Cancer

“…Some differentially expressed RNAs and proteins in exosomes have been identified as potential biomarkers linked to CRC initiation and progression. Wang et al considered that CRC cell-derived exosomal miR-146a-5p and miR-155-5p could activate the JAK2-STAT3/NF- κ B signaling pathways, thereby enhancing the invasive ability of CRC cells [ 33 ]. Studies have found that in human CRC cells, exosomal Nrf2 plays a pivotal role in oxaliplatin resistance [ 34 ].…”

Macrophage-Derived Extracellular Vesicles: A Promising Tool for Personalized Cancer Therapy

“…CAFs actively contribute to tumor progression by providing physical support to cancer cells (in association with ECM) and releasing several factors, such as VEGF and FGF, that stimulate the angiogenesis [ 29 ]. These cells also play a crucial role during the metastatic processes by the activation of several pathways, including the release of different enzymes able to induce ECM degradation, and then improving cellular migration and invasiveness [ 30 , 31 ]. The ECM is a “cell-derived scaffold” and is a pivotal physical support for all tissues in the human body (except for circulating cells) [ 32 ].…”