IL-22 is related to development of human colon cancer by activation of STAT3

Abstract

BackgroundIt has been previously reported that IL-22, one of the cytokines secreted by Th17 cells, demonstrates both a protective and inflammatory promotion effect in inflammatory bowel disease (IBD) through STAT3 signaling activation. We sought to investigate the role of IL-22 expression in colon cancer (CC).MethodsThe expression of IL-22 and related molecules were detected in human CC, the detail function and mechanism of IL-22 were investigated by in vivo and in vitro model.ResultsOur results demonstrated significant upregulation of IL-22 in human CC tumor infiltrated leukocytes (TILs) compared to peripheral lymphocytes. Moreover, our findings demonstrated that IL-22 expression was significantly higher in ulcerative colitis (UC) tissues versus normal colon tissues. Both IL-22 receptor α1 (IL-22RA1) and IL-23 were highly expressed in CC and UC tissues compared to normal controls. TILs exhibiting various IL-22 expression levels isolated from CC patients were demonstrated to enhance tumor growth and metastasis co-transplanted with Hct-116 cells underwent subcutaneous transplantation in mice model. Tumor growth and metastasis was promoted by STAT3 phosphorylation and upregulation of its downstream genes such as Bcl-xl, CyclinD1, and VEGF. In vitro studies confirmed the anti-apoptotic and pro-proliferation effect of IL-22 according to the BrdU cooperation assay and peroxide induced apoptosis analysis with or without the presence of IL-22.ConclusionIn this study we demonstrated that excessive IL-22 in the CC and UC microenvironment leads to tumor growth, inhibition of apoptosis, and promotion of metastasis depend on STAT3 activation.

Th22 cells control colon tumorigenesis through STAT3 and Polycomb Repression complex 2 signaling

“…[1][2][3][4] It has been reported that IL-22 is predominantly expressed by CD4 C T cells in the human colorectal cancer microenvironment. [5][6][7][8] As its receptor is only expressed on epithelial cells, 9 it is reasonable that IL-22 protects epithelial mucosa from bacterial infection and inflammation damage in mouse models. [10][11][12] We have recently reported that human Th22 cells are recruited into the colon cancer microenvironment and promote colon cancer stemness through STAT3-dependent pathway.…”

Innate Immune Cells in Inflammation and Cancer

“…IL-22 has been shown to promote colitis, which is associated with mucosal hyperplasia (41). Furthermore, results from several recent articles have shown that IL-22 can also promote tumorigenesis in the intestine (42,(82)(83)(84)(85). Accordingly, IL-22 needs to be carefully controlled, and this regulation can be exerted by DCs in the intestine by at least two mechanisms.…”

TGF-β: Its role in the differentiation and function of T regulatory and effector cells

“…Recent studies also demonstrated that the level of Th22 cells and IL-22 increased in infection sites (Zheng et al, 2008b), in inflamed intestines of IBD or CD patients (Andoh et al, 2005;Wolk et al, 2007), and in primary tumor tissue (Jiang et al, 2011(Jiang et al, , 2013. Thus, it has been suggested that IL-22 and Th22 cells may be important for the pathogenesis of these skin and mucosa diseases.…”