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

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.

MicroRNAs in Colon Tissue of Pediatric Ulcerative Pancolitis Patients Allow Detection and Prognostic Stratification

“…Although IBD’s exact pathogenesis remains unclear, its inflammatory nature is evident also from miRNAs that are repeatedly identified as deregulated in IBD patients of either subtype [ 12 ]. Potential involvement of those miRNAs can be traced to the most essential pathways and agents of systemic inflammatory response, such as TLR/NF-κB, TNF-α and other pro- and anti-inflammatory factors, either as their regulators (as in the case of miR-375,3 miR-223 [ 21 , 22 ], let-7i [ 23 ], miR-200b and the entire miR-200 family [ 24 , 25 ] and miR-146a [ 26 ]) or as the molecules regulated by such pro- and anti-inflammatory agents, such as miR-142 [ 27 , 28 ]. Closely related to inflammation seems to be autophagy, a natural process of removing certain cellular components.…”

IL-10 and IL-22 in Mucosal Immunity: Driving Protection and Pathology

“…Conversely, data also shows that IL-22 results in tumor progression ( 135 , 136 ). With the elevated IL-17 and IL-22 levels in STAT1 −/− mice, the colonic epithelial cell proliferation increases while the tumor apoptosis rate decreases in the early stage of tumor formation ( 137 ). In humans, an SNP variation in the human IL-22 gene greatly increases the risk of colon cancer ( 138 ).…”

Transmembrane and Ubiquitin-Like Domain Containing 1 Protein (TMUB1) Negatively Regulates Hepatocellular Carcinoma Proliferation via Regulating Signal Transducer and Activator of Transcription 1 (STAT1)

“…STAT1 (signal transducer and activator of transcription 1) is a key member of the mammalian STAT family and transduces signals from the cytoplasm to the nucleus for regulating gene expression [17]. Current research indicates that STAT1 has inhibitory effects on a variety of tumors such as colon (rectal) cancer [18], HCC [19,20], soft tissue sarcoma, pancreatic cancer, esophageal cancer, and metastatic melanomas [21–24]. STAT1 not only inhibits tumorigenesis but also inhibits tumor cell proliferation, promotes apoptosis, inhibits angiogenesis, and regulates tumor immunity [24].…”