Dataset Information

MiR-126 downregulates CXCL12 expression in intestinal epithelial cells to suppress the recruitment and function of macrophages and tumorigenesis in a murine model of colitis-associated colorectal cancer.

ABSTRACT: Inflammatory bowel disease, characterised by chronic relapsing-remitting colitis, is a significant risk factor for colorectal cancer (CRC). Previously, we showed that miR-126 functions as a tumour suppressor in CRC and is inversely correlated with tumour proliferation, metastasis and patient prognosis. In the current study, we documented a protective role for miR-126 in colitis-associated CRC (CAC) and its underlying mechanism. We detected downregulated miR-126 expression during colorectal tumorigenesis in the mouse CAC model and in specimens from patients with CRC. The deficiency of miR-126 in intestinal epithelial cells (IECs) exacerbated tumorigenesis in mice. We identified CXCL12 as a direct target of miR-126 in inhibiting the development of colitis and CAC. Moreover, miR-126 regulated the recruitment of macrophages via CXCL12 and decreased the levels of proinflammatory cytokines (IL-6, IL-12 and IL-23). In addition, IL-6 secreted by macrophages, which were regulated by cocultured transfected CRC cells, altered the proliferation and migration of colon cells. Our data suggest that miR-126 exerts an antitumour effect on CAC by regulating the crosstalk between IECs and macrophages via CXCL12-IL-6 signalling. Our study contributes to the understanding of cancer progression and suggests miR-126 as a potential therapy for CRC.

SUBMITTER: Wu S

PROVIDER: S-EPMC9533691 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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miR-126 downregulates CXCL12 expression in intestinal epithelial cells to suppress the recruitment and function of macrophages and tumorigenesis in a murine model of colitis-associated colorectal cancer.

Wu Shuai S Yuan Wei W Luo Weiwei W Nie Kai K Wu Xing X Meng Xiangrui X Shen Zhaohua Z Wang Xiaoyan X

Molecular oncology 20220411 19

Inflammatory bowel disease, characterised by chronic relapsing-remitting colitis, is a significant risk factor for colorectal cancer (CRC). Previously, we showed that miR-126 functions as a tumour suppressor in CRC and is inversely correlated with tumour proliferation, metastasis and patient prognosis. In the current study, we documented a protective role for miR-126 in colitis-associated CRC (CAC) and its underlying mechanism. We detected downregulated miR-126 expression during colorectal tumor ...[more]

PMID: 35363937

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Project description:BackgroundHuman interleukin-22 (IL-22) is known as a "dual function" cytokine that acts as a master regulator to maintain homeostasis, structural integrity of the intestinal epithelial barrier, and shielding against bacterial pathogens. On the other hand, the overexpression of IL-22 is associated with hyper-proliferation and recruitment of pathologic effector cells, leading to tissue damage and chronic inflammation in specific diseases including inflammatory bowel disease (IBD). To study a role of IL-22-mediated signaling axis during intestinal inflammation, we generated a set of small protein blockers of IL-22R1 and verified their inhibitory potential on murine model of colitis.MethodsWe used directed evolution of proteins to identify binders of human IL-22 receptor alpha (IL-22R1), designated as ABR ligands. This approach combines the assembly of a highly complex combinatorial protein library derived from small albumin-binding domain scaffold and selection of promising protein variants using ribosome display followed by large-scale ELISA screening. The binding affinity and specificity of ABR variants were analyzed on transfected HEK293T cells by flow cytometry and LigandTracer. Inhibitory function was further verified by competition ELISA, HEK-Blue IL-22 reporter cells, and murine dextran sulfate sodium (DSS)-induced colitis.ResultsWe demonstrate that ABR specifically recognizes transgenic IL-22R1 expressed on HEK293T cells and IL-22R1 on TNFα/IFNγ-activated HaCaT cells. Moreover, some ABR binders compete with the IL-22 cytokine and function as IL-22R1 antagonists in HEK-Blue IL22 reporter cells. In a murine model of DSS-induced acute intestinal inflammation, daily intraperitoneal administration of the best IL-22R1 antagonist, ABR167, suppressed the development of clinical and histological markers of colitis including prevention of mucosal inflammation and architecture deterioration. In addition, ABR167 reduces the DSS-induced increase in mRNA transcript levels of inflammatory cytokines such as IL-1β, IL-6, IL-10, and IL-17A.ConclusionsWe developed small anti-human IL-22R1 blockers with antagonistic properties that ascertain a substantial role of IL-22-mediated signaling in the development of intestinal inflammation. The developed ABR blockers can be useful as a molecular clue for further IBD drug development.

Dataset Information

MiR-126 downregulates CXCL12 expression in intestinal epithelial cells to suppress the recruitment and function of macrophages and tumorigenesis in a murine model of colitis-associated colorectal cancer.

Publications

miR-126 downregulates CXCL12 expression in intestinal epithelial cells to suppress the recruitment and function of macrophages and tumorigenesis in a murine model of colitis-associated colorectal cancer.

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