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

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

Cancers (2018-09-22)
Sonia Leon-Cabrera, Armando Vázquez-Sandoval, Emmanuel Molina-Guzman, Yael Delgado-Ramirez, Norma L Delgado-Buenrostro, Blanca E Callejas, Yolanda I Chirino, Carlos Pérez-Plasencia, Miriam Rodríguez-Sosa, Jonadab E Olguín, Citlaltepetl Salinas, Abhay R Satoskar, Luis I Terrazas
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Azoxymethane, 13.4 M, ≥98%