STAT1 Is Required for Decreasing Accumulation of Granulocytic Cells via IL-17 during Initial Steps of Colitis-Associated Cancer.

Yael Delgado-Ramirez,Blanca E Callejas,Itzel Medina-Andrade,Luis I Terrazas,Yamileth Martinez,Itzel Baltazar-Perez,Sonia Leon-Cabrera,Norma L Delgado-Buenrostro,Jonadab E Olguín,Yolanda I Chirino

doi:10.3390/ijms22147695

Abstract

Signal transducer and activator of transcription 1 (STAT1) acts as a tumor suppressor molecule in colitis-associated colorectal cancer (CAC), particularly during the very early stages, modulating immune responses and controlling mechanisms such as apoptosis and cell proliferation. Previously, using an experimental model of CAC, we reported increased intestinal cell proliferation and faster tumor development, which were consistent with more signs of disease and damage, and reduced survival in STAT1-/- mice, compared with WT counterparts. However, the mechanisms through which STAT1 might prevent colorectal cancer progression preceded by chronic inflammation are still unclear. Here, we demonstrate that increased tumorigenicity related to STAT1 deficiency could be suppressed by IL-17 neutralization. The blockade of IL-17 in STAT1-/- mice reduced the accumulation of CD11b+Ly6ClowLy6G+ cells resembling granulocytic myeloid-derived suppressor cells (MDSCs) in both spleen and circulation. Additionally, IL-17 blockade reduced the recruitment of neutrophils into intestinal tissue, the expression and production of inflammatory cytokines, and the expression of intestinal STAT3. In addition, the anti-IL-17 treatment also reduced the expression of Arginase-1 and inducible nitric oxide synthase (iNOS) in the colon, both associated with the main suppressive activity of MDSCs. Thus, a lack of STAT1 signaling induces a significant change in the colonic microenvironment that supports inflammation and tumor formation. Anti-IL-17 treatment throughout the initial stages of CAC related to STAT1 deficiency abrogates the tumor formation possibly caused by myeloid cells.

Highlights

The tumor suppression function of Signal transducer and activator of transcription 1 (STAT1) has been associated with cell growth arrest, apoptosis, and inhibition of angiogenesis, but our studies suggest that STAT1 plays an important role in immune response modulation during inflammation-associated cancer
Our study reveals that the effect of host STAT1 deficiency on tumor development can be reversed upon IL-17-blockade treatment, which correlates with a decreased accumulation of CD11b+ Ly6Clow Ly6G+ cells and neutrophils and a remarkable reduction in tumor growth
We determined that STAT1 deficiency rapidly hastens the development of CAC through an azoxymethane (AOM)/dextran sodium sulfate (DSS) regiment, with greater histological damage and increased cell proliferation, as well as reduced apoptosis, during early CAC development, which affects the animal’s chance of survival [8]

Summary

Introduction

Signal transducer and activator of transcription 1 (STAT1) is part of the Janus kinase (JAK/STAT) signaling pathway and mediates important events associated with mucosal homeostasis, intestinal immune function, and cancer progression. Many lines of evidence suggest that STAT1 acts as a tumor suppressor molecule in various malignancies [1,2], prompting antiproliferative and proapoptotic responses and enhancing antitumor immunity [2]. Colitis-associated colorectal cancer (CAC) frequently develops in subjects with inflammatory bowel diseases (IBDs), such as ulcerative colitis (UC) and Crohn’s disease (CD) [3]. Colon cancer patients with high STAT1 expression have better clinical outcomes than those with low STAT1 expression in the colon tissue [4,5,6]. A reduction in STAT1 expression and/or a loss of its activation occurs in malignant colorectal cancer cells [7]

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