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.
Highlights
It 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
Excessive IL-22 in tissues of colon cancer and ulcerative colitis In order to investigate the expression of IL-22 in human colon cancer, tumor infiltrated leukocytes (TILs), which are the principal source of IL-22, were isolated from excised fresh tumor tissues
Significant high expression of IL-22 were detected by real-time PCR in the TILs samples compared to peripheral blood mono-nuclear cells (PBMCs) (P = 0.00618, P < 0.01, by unpaired t-test) (Figure 1A)
Summary
It 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. After 40 years of UC, approximately 25–30% of patients will have developed CC [3] Both UC and CC exhibit a much of the growth that stimulates the cross-talk between immune and IECs or malignant cells is mediated by cytokines that activate the oncogenic transcription factor STAT3 [5], a major intrinsic activator in cancer inflammation and a regulator of the tumor microenvironment [6,7]. It has been previously demonstrated that specific ablation of STAT3 in intestinal epithelial cells suppresses cell proliferation and reduces tumor incidence in both a DSS-induced colitis model and colitis associated cancer (CAC) model [10,11]. Enhanced STAT3 activation has been shown to exhibit an accelerating effect on CAC development by mutation of the gp130 receptor [10]
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