Deficiency in STAT1 Signaling Predisposes Gut Inflammation and Prompts Colorectal Cancer Development.

Sonia Leon-Cabrera,Blanca Callejas,Luis Terrazas,Yael Delgado-Ramirez,Abhay Satoskar,Emmanuel Molina-Guzman,Yolanda Chirino,Norma Delgado-Buenrostro,Miriam Rodríguez-Sosa,Jonadab Olguín,Carlos Pérez-Plasencia,Citlaltepetl Salinas,Armando Vázquez-Sandoval

doi:10.3390/cancers10090341

Abstract

Signal transducer and activator of transcription 1 (STAT1) is part of the Janus kinase (JAK/STAT) signaling pathway that controls critical events in intestinal immune function related to innate and adaptive immunity. Recent studies have implicated STAT1 in tumor–stroma interactions, and its expression and activity are perturbed during colon cancer. However, the role of STAT1 during the initiation of inflammation-associated cancer is not clearly understood. To determine the role of STAT1 in colitis-associated colorectal cancer (CAC), we analyzed the tumor development and kinetics of cell recruitment in wild-type WT or STAT1−/− mice treated with azoxymethane (AOM) and dextran sodium sulfate (DSS). Following CAC induction, STAT1−/− mice displayed an accelerated appearance of inflammation and tumor formation, and increased damage and scores on the disease activity index (DAI) as early as 20 days after AOM-DSS exposure compared to their WT counterparts. STAT1−/− mice showed elevated colonic epithelial cell proliferation in early stages of injury-induced tumor formation and decreased apoptosis in advanced tumors with over-expression of the anti-apoptotic protein Bcl2 at the colon. STAT1−/− mice showed increased accumulation of Ly6G+Ly6C−CD11b+ cells in the spleen at 20 days of CAC development with concomitant increases in the production of IL-17A, IL-17F, and IL-22 cytokines compared to WT mice. Our findings suggest that STAT1 plays a role as a tumor suppressor molecule in inflammation-associated carcinogenesis, particularly during the very early stages of CAC initiation, modulating immune responses as well as controlling mechanisms such as apoptosis and cell proliferation.

Highlights

Colorectal cancer is one of the most frequent neoplasms and is the second most common cause of death by cancer in Western countries [1]
We evaluated the course of the disease for 20, 40, and 68-day periods in Signal transducer and activator of transcription 1 (STAT1)−/− and WT mice (Figure 1A) as an approximation of different stages of tumor progression
AOM/dextran sodium sulfate (DSS) administration in STAT1−/− mice resulted in significantly reduced early survival during the first and third DSS cycles (Figure 1D)

Summary

Introduction

Colorectal cancer is one of the most frequent neoplasms and is the second most common cause of death by cancer in Western countries [1]. Colitis-associated colon cancer (CAC), which develops under chronic inflammatory conditions in the intestinal tissue, is different from sporadic cancer and is one of the most frequent causes of morbidity and mortality in inflammatory bowel disease (IBD) patients [2,3]. Ulcerative colitis (UC) and Crohn’s disease (CD) are considered the main components of human IBD. Patients with UC have an increased risk of developing CAC, and the extent and duration of the disease augment its threat. CAC is considered to have greater malignant potential than sporadic colorectal cancer and patients show poor survival rates in the advanced stages [6]. The immunological mediators underlying the development and progression of colorectal cancer preceded by chronic inflammation are still unclear

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