IL-22 promotes the proliferation of cancer cells in smoking colorectal cancer patients

Abstract

Chronic cigarette smoking increases the risk of developing colorectal cancer (CRC) and causes higher mortality of CRC patients. To improve our understanding of the underlying mechanism and devise treatment strategies specifically targeted at chronic smoking CRC patients, we examined the immune system of healthy and CRC patients who are complete nonsmokers or chronic primary smokers. We found that the serum concentrations of CRC nonsmokers and CRC smokers were skewed toward Th17-type cytokines, including interleukin (IL)-17 and IL-22. Notably, smoking CRC subjects had significantly higher levels of IL-22 than nonsmoking CRC patients. We also observed higher percentages of CCR4(+)CCR6(+) Th17 cells in circulating blood and higher secretion of IL-17 and IL-22 by peripheral blood mononuclear cells (PBMCs) of nonsmoking CRC and smoking CRC patients, compared to healthy individuals. Again, we observed elevated IL-17 and IL-22 secretion by CRC smokers than nonsmokers. Since IL-22 has been shown to stimulate tumorigenesis, which was also replicated in our experiments using cancer cell line model, we tested whether CRC patients' cell culture supernatant could also support tumor growth using this model. We found that both HT29 cells and LoVo cells had the highest proliferation in the supernatant from smoking CRC patients. Moreover, the proliferation of LoVo cells in smoking CRC supernatant was significantly higher than that in nonsmoking CRC supernatant. In addition, we found that the IL-22 concentration in normal gut tissue of the smoking CRC patients was significantly increased compared to that in nonsmoking CRC subjects, while no significant differences were observed in tumor tissues. Our results suggest that chronic smokers may have higher risk for CRC and worse prognosis due to dysregulated IL-22 production.

A catch‐22: Interleukin‐22 and cancer

“…Smokers with colorectal cancer show higher IL‐22 production by PBMC and within their mucosae but not within the tumor tissue. Treatment of cell lines with serum from these patients increased their proliferation .…”

Smoking as a risk factor for colorectal neoplasms in young individuals? A systematic meta-analysis

“…Nicotine downregulated micro ribonucleic acid-200c (miR-200c) to promote growth and metastasis of CRC in various human CRC cell lines [ 40 ]. It has been reported that the cytokine interleukin-22 (IL-22) could not only protect the intestinal epithelium integrity but was also related to the occurrence and development of CRC by various pathways [ 41 ]. Aryl hydrocarbon receptor (AHR), which is sensitive to polycyclic aromatic hydrocarbons controls interleukin 22 production by T helper 17 cells (Th17) and T helper cells type 22 (Th22) [ 42 , 43 ].…”

Rationalizing heptadecaphobia: TH17 cells and associated cytokines in cancer and metastasis

“…Mechanistically, IL‐22 can protect both malignant epithelial cells and healthy epithelial stem cells from extracellular and intracellular threats, leading to both pro‐ [96] and antitumorigenic [48] effects. Furthermore, IL‐22 signaling increased colonic cancer cell proliferation [97,98], partially by synergizing with mutated KRAS [99]. Additionally, IL‐22 can induce an upregulation of nicotinamide N‐methyltransferase and CEA gene expression in multiple cancer cell lines, promoting proliferation and migration in turn [100].…”

“…Two-colored boxes indicate divergent functions. In general, current literature suggests a pro-tumorigenic role of IL-17A [59][60][61][62][63][64][65][66][67][69][70][71]74,76,[78][79][80][81] and that IL-22 might exert tumor-supporting [47,[86][87][88][89]92,[96][97][98][99][100] and tumor-inhibiting effects [47,48] in CRC. (A) T H 17 cells and cd T cells mark major producers of IL-17A during colon carcinogenesis [66][67][68].…”

“…For example, the signaling of IL-22 on healthy epithelial cells can protect from genotoxic stress, leading to antitumorigenic functions [47]. However, signaling on cancer cells may increase cell proliferation and migration, cumulating in overall protumorigenic effects [96][97][98][99][100]. Functions of IL-17F in CRC remain largely elusive and are not displayed in this figure . tumor growth [66].…”