IFIH1-deficiency promotes tumor development in the intestine

Background:

Chronic inflammation such as in patients with inflammatory bowel diseases (IBD) induces DNA mutations and promotes malignant cellular transformation. The IBD susceptibility locus Interferon-induced with helicase C domain 1 (IFIH1) is a cytosolic pattern recognition receptor for viral long dsRNA inducing the secretion of type I interferons (IFNs). Besides its antiviral properties, IFNs play a major role in homeostasis and antitumor immunity, either by direct effects on tumor cells or indirectly via eliciting antitumor immune responses. This study aims to elucidate the role of IFIH1 in intestinal tumorigenesis.

Methods:

Cancer development in wildtype (wt) and Ifih1^–/– mice was investigated in colitis-associated cancer (CAC) models and in genetic models for intestinal cancer. Spontaneous tumor formation was assessed in the Interleukin (IL)-10 model of chronic colitis. The impact of the carcinogen azoxymethane (AOM) was examined using the AOM/DSS model. Finally, we investigated the interplay between IFIH1 and the tumor suppressor Adenomatous Polyposis Coli (APC) by generating Ifih1^–/–/APC^min+ mice as a genetic model for carcinogenesis.

Results:

In the absence of Ifih1, chronic inflammation per se was sufficient to induce colonic tumors in IL10/Ifih1 double-knockout mice but not in IL10^-/- animals. The additional application of a carcinogen in the context of intestinal inflammation strongly aggravated disease phenotypes and mortality in Ifih1 mice compared to wt mice. Furthermore, Ifih1^–/–/APC^min+ mice were highly susceptible to intestinal cancer development. Collectively, Ifih1^–/– mice displayed significantly higher tumor numbers and tumor areas compared to wt or IL10^-/- animals.

Conclusion:

Our results indicate, that IFIH1 plays a major role in the restriction of intestinal carcinogenesis. The similar outcome in CAC models and genetic cancer models suggests, that IFIH1 acts as pleiotropic protein involved in processes including homeostasis, immunomodulation and cell proliferation. Thus, the deeper understanding of IFIH1's contribution to intestinal tumorigenesis could pave the way for new therapeutic strategies.