Abstract
Colitis-associated colon cancer (CAC) is one of the most common malignant neoplasms and a leading cause of death. The immunologic factors associated with CAC development are not completely understood. Signal transducer and activator of transcription 6 (STAT6) is part of an important signaling pathway for modulating intestinal immune function and homeostasis. However, the role of STAT6 in colon cancer progression is unclear. Following CAC induction in wild-type (WT) and STAT6-deficient mice (STAT6-/-), we found that 70% of STAT6-/- mice were tumor-free after 8 weeks, whereas 100% of WT mice developed tumors. STAT6-/- mice displayed fewer and smaller colorectal tumors than WT mice; this reduced tumorigenicity was associated with decreased proliferation and increased apoptosis in the colonic mucosa in the early steps of tumor progression. STAT6-/- mice also exhibited reduced inflammation, diminished concentrations COX2 and nuclear β-catenin protein in the colon, and decreased mRNA expression of IL17A and TNFα, but increased IL10 expression when compared with WT mice. Impaired mucosal expression of CCL9, CCL25, and CXCR2 was also observed. In addition, the number of circulating CD11b+Ly6ChiCCR2+ monocytes and CD11b+Ly6ClowLy6G+ granulocytes was both decreased in a STAT6-dependent manner. Finally, WT mice receiving a STAT6 inhibitor in vivo confirmed a significant reduction in tumor load as well as less intense signs of CAC. Our results demonstrate that STAT6 is critical in the early steps of CAC development for modulating inflammatory responses and controlling cell recruitment and proliferation. Thus, STAT6 may represent a promising target for CAC treatment. Cancer Immunol Res; 5(5); 385-96. ©2017 AACR.
Highlights
Chronic inflammation is widely associated with increased susceptibility to developing colorectal cancer [1]
We evaluated the role of Signal transducer and activator of transcription 6 (STAT6) in developing colitis-associated colon cancer (CAC) using the azoxymethane (AOM)/dextran sodium sulfate (DSS) model, examining the dependence of colonic inflammation, epithelial cell proliferation and apoptosis, and monocytic-granulocytic recruitment on STAT6 signaling
Previous studies have shown that STAT6 is involved in intestinal epithelial homeostasis and its activity is correlated with colon cancer cell growth in vitro [19, 20], yet the role of STAT6 has not been extensively studied in the early steps of CAC
Summary
Chronic inflammation is widely associated with increased susceptibility to developing colorectal cancer [1]. Patients with inflammatory bowel diseases such as Crohn's disease and ulcerative colitis (UC), which are characterized by prolonged inflammation of the intestine, have an increased risk of developing colorectal cancer [2]. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/). Delay colorectal cancer, suggesting the involvement of inflammatory pathways in tumor progression [3]. In a genetically susceptible host, epithelial barrier breakdown could result in magnified responses to microbial products, leading to chronic inflammation and tumorigenesis. Proinflammatory cytokines produced in response to commensal bacteria can create a microenvironment that enhances epithelial cell proliferation, angiogenesis, and increased susceptibility to mutations [1]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
