Interleukin‐13 and its signaling pathway is associated with obesity‐related colorectal tumorigenesis

Abstract

The incidence of colorectal cancer (CRC) has been on the rise, which is linked to the increasing prevalence of obesity, based on global epidemiological evidence. Although chronic inflammation is implicated in tumor development, the mechanisms underlying obesity‐associated CRC remain unknown. Here, we sought to identify the inflammatory cytokines and their roles in obesity‐related colorectal tumorigenesis using cytokine array analyses in a mouse model. Colorectal tumorigenesis was induced through i.p. injection of azoxymethane once a week for 6 weeks in 6‐week‐old female WT C57Black/6J mice and the obesity diabetes model mouse KK/TaJcl, KK‐Ay/TaJcl. The formation of aberrant crypt foci and colorectal tumors were more frequent in obese mice compared with WT mice, and both serum interleukin (IL)‐13 and IL‐13 receptor (R) expression in the normal intestinal mucosal epithelium were significantly increased in the obese mice. Furthermore, addition of IL‐13 to a human CRC cell line and a human colon organoid culture altered the phenotype of intestinal epithelial cells. Knockdown experiments further revealed that IL‐13Rα1 dominantly induced mucosal proliferation. Collectively, These results suggest an association between anti‐inflammatory cytokines and colorectal carcinogenesis, and provide new research directions for cancer prevention strategies. In particular, inflammation provoked by obesity, notably by increased expression of the cytokine IL‐13, could play an important role in the carcinogenesis of obesity‐related CRC.

Interleukins 4 and 13 and Their Receptors Are Differently Expressed in Gastrointestinal Tract Cancers, Depending on the Anatomical Site and Disease Advancement, and Improve Colon Cancer Cell Viability and Motility

“…Stimulation with IL-13 downregulated PTGS2 expression in HT-29 cells and reduced that of HIF1A, although IL13 in clinical samples was correlated positively with VEGFA, a HIF1α-inducible key mediator of angiogenesis. Nonetheless, contradicting the implied protective role [23], animal studies have implicated IL-13 in the development of metaplasia during gastric carcinogenesis (reviewed in [22]) and obesity-related CRC [18] while our own results have shown systemic interleukin to be elevated in both CRC [39] and high-risk conditions [46].…”

“…A pro-proliferative activity of IL-4 toward HT-29 and HCT 116 cells was reported by Keller et al [20]. In turn, pro-proliferative activity of IL-13 toward HT-29 was recently corroborated by Matsui et al [18]. The results of Chang et al [28] implicated that the dual IL-4 effect on proliferation might depend on whether the interleukin activates STAT1 (anti-proliferative) or STAT6 (pro-proliferative) as previously found in helper T cells [63].…”

“…In turn, the upregulation of IL-13Rα2 has been reported in colorectal [10] and gastric [16] cancers and linked with local advancement and metastasis [10] as well as poor prognosis [10,16]. Corroborating potentially tumor-promoting role also for IL-13Rα1, Matsui et al [18] demonstrated co-expression of the receptor with proliferation indices in mice with obesity-related CRC. Moreover, the authors showed an inhibition of colonic cancer cell proliferation induced by IL-13 by silencing IL13Ra1, but not IL13Ra2 gene.…”

Polymorphisms in Interleukin 13 Signaling and Interacting Genes Predict Advanced Fibrosis and Hepatocellular Carcinoma Development in Non-Alcoholic Steatohepatitis

“…Interestingly, recent reports proved that IL-13 may play a crucial role in other tumors. Whereas, IL-13 was proved to be associated with obesity-related colorectal tumorigenesis [39]. Inflammation provoked by obesity notably increased expression of IL-13, which in turn leads to increased expression of IL-13R1, ending up with activation of downstream phosphorylation of the transcription factor STAT6, suggesting a possible mechanism of carcinogenesis in colon cancer [40].…”

Role of Overweight and Obesity in Gastrointestinal Disease

“…Among several factors, a very recent population based study carried out in the USA confirmed that obesity, diabetes mellitus, family history of other malignancy, and smoking independently increase the odds ratio for the occurrence of colorectal cancer [83]. Inflammatory cytokines appear to play a key role in linking obesity and colorectal carcinogenesis particularly so for IL-6 and tumor necrosis factor-α [84,85]; a recent study also describing IL-13 as a potential factor involved in the development of obesity-related colon cancer onset [86]. As it was the case for colon rectal cancer, also for the gastro-esophageal cancer a positive relationship between abdominal obesity and cancer occurrence has been described.…”