M2 macrophage-derived exosomal microRNA-155-5p promotes the immune escape of colon cancer by downregulating ZC3H12B

Abstract

Previous evidence has highlighted M2 macrophage regulation of cancer cells via exosome shuttling of microRNAs (miRNAs or miRs). The current study set out to explore the possible role of M2 macrophage-derived exosomal miR-155-5p in regard to immune escape of colon cancer cells. Experimental data from quantitative reverse-transcriptase PCR (qRT-PCR) and western blot analysis revealed highly expressed miR-155-5p and interleukin (IL)-6 and poorly expressed ZC3H12B in M2 macrophagederived exosomes. Additionally, miR-155-5p could be transferred by M2 macrophage-isolated exosomes to colon cancer cells, which targeted ZC3H12B by binding to the 3¿ UTR, as identified by dual luciferase reporter gene. Meanwhile, gain-and lossof function experimentation on miR-155-5p and ZC3H12B in SW48 and HT29 cells cocultured with M2 macrophage-secreted exosomes demonstrated that miR-155-5p overexpression or ZC3H12B silencing promoted the proliferation and antiapoptosis ability of SW48 and HT29 cells, as well as augmenting the CD3 + T cell proliferation and the proportion of interferon (IFN)-g + T cells. Xenograft models confirmed that M2 macrophage-derived exosomal miR-155-5p reduced the ZC3H12B expression to upregulate IL-6, which consequently induced immune escape and tumor formation. Collectively, our findings indicated that M2 macrophage-derived exosomal miR-155-5p can potentially promote the immune escape of colon cancer by impairing ZC3H12B-mediated IL-6 stability reduction, thereby promoting the occurrence and development of colon cancer.

Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): From Mechanism to Therapy and Prognosis

“…Obesity-induced IL-6 expression promotes the polarization of M2 macrophages and induces secretion of the chemokine CC-chemokine ligand 20 (CCL20) in the CAC microenvironment; CCL20 recruits CC-chemokine receptor 6 (CCR6)-expressing B cells and γδ T cells via chemotaxis, leading to CAC progression [51]. It has been reported that exosomal miR-155-5p derived from M2 macrophages can accelerate the occurrence and development of colon cancer via its effect on ZC3H12B-mediated IL-6 stability [52]. Exosomal miR-1246, secreted by colon tumor spheres, increased the proportion of M2 polarized macrophages in vitro [53].…”

Exosome-Mediated Crosstalk Between Tumor and Tumor-Associated Macrophages

“…Mechanically, AGAP2-AS1 negatively regulates miR-296, and NOTCH2 is targeted by miR-296. Thus, M2 macrophage-derived exosomal AGAP2-AS1 enhances radiotherapy immunity in lung cancer by reducing miR-296 and elevating NOTCH2 (Zhang F. et al, 2021).…”

“…M2 macrophage-derived exosomal miR-155-5p promotes the development of colon cancer by inhibiting the expression of ZC3H12B in vivo . Delivery of miR-155-5p from M2 macrophage to colon cancer cells through exosomes impaires ZC3H12B-mediated IL-6 stability reduction, which consequently induced immune escape and tumor formation ( Ma et al, 2021 ).…”

“…Depending on the cell of origin, exosomes contain many constituents of a cell, including DNA, RNA, lipids, metabolites, and cytosolic and surface proteins ( Kalluri and LeBleu, 2020 ). It has been demonstrated that exosomes are associated with immune response and cancer progression ( Li Z. et al, 2020 ; Ma et al, 2021 ; Schwarzenbach and Gahan, 2021 ). The components delivered by exosomes to recipient cells result in the alteration of biological response, which can be disease-promoting or restraining.…”

Exosomes in the Tumor Microenvironment: From Biology to Clinical Applications

“…In this sense, lung cancer cell-derived exosomes (from the A59 and H358 cell lines) alter the transcriptional and bioenergetic signature of M0 macrophages, leading them to an M2 phenotype [142]. However, the M2 macrophage-derived exosomes can transfer miR-21-5p and miR-155-5p to cancer cells, promoting the downregulation of transcription factor Brahma-related gene-1 (BRG1), leading to cell migration and invasion in colon cancer cells [141,143]. Gastric cancer showed similar results; M2 macrophage-derived exosomemediated apolipoprotein E (ApoE) transfer was found to increase the cancer cell migration in a PI3K/Akt signaling pathway activation-dependent manner [144].…”