Deficiency of Interferon-Gamma or Its Receptor Promotes Colorectal Cancer Development

Abstract

Genetic variations in interferon-gamma (IFN-γ) and its receptor (IFNγR) subunits are closely associated with the risk of colorectal cancer (CRC) and survival after diagnosis. However, the role of loss of IFN-γ or IFNγR function in the pathogenesis of CRC remains unclear. Here, we investigated the role of endogenous IFN-γ deficiency in adenomatous polyposis coli (Apc)-mediated intestinal tumor by developing a variant of Apc(Min/+) mice. The Apc(Min/+)IFN-γ(+/-) mice presented with increased number and size of adenomas, and 41.7% of these mice developed adenocarcinoma. Molecular analyses of the adenomas suggested that heterozygous deletion of IFN-γ promoted EGFR/Erk1/2 and Wnt/β-catenin signaling. In vitro, IFN-γ administration inhibited Apc-mutated HT-29 colon cancer cell proliferation and had no effect on the proliferation of HCT-116 colon cancer cells that express wild-type Apc. Besides, we challenged HT-29 cells with small interfering RNA targeting one of its receptor subunits IFNγR1. We found that knockdown of IFNγR1 in HT-29 cells stimulated cell proliferation and colony formation, which was also related to the regulation of EGFR/Erk1/2 and Wnt/β-catenin signaling. Thus, our results strongly support the notion that IFN-γ and IFNγR1 act as a rate-limiting factor in the development of CRC, uncovering a novel role for them in cancer biology.

Lack of interferon-γ receptor results in a microenvironment favorable for intestinal tumorigenesis

“…Increased tumorigenesis was also reported in IFN-γ +/− Apc Min/+ mice [27]. Therefore, it appears that deficiency in either the IFN-γ receptor or its ligand would lead to increased intestinal tumorigenesis.…”

The Immune Response Against Oryzatensin Increase VEGF and MMP-9 Experssion in HEP-G2 Cell Line

“…IFN-γ promotes the CD4+ naïve T lymphocytes to differentiate toward the Th1 and inhibits the differentiation of Th2. Some mutations in the receptors of IFN-γ increase cancer risk [17][18][19].…”

A plant-made cholera toxin B subunit enhances mucosal wound healing and protects against ulcerative colitis and colon cancer.

“…Our results showed increased Ifnγ gene expression and IFNγ protein levels (Fig. 5.3 and 5.4) , which is considered an anti-tumor cytokine while helping to maintain the intestinal epithelial barrier (165). Additionally, CTBp decreased tumor number but within this tumor number we also significantly decreased tumor size.…”

“…Ifnγ, Csf2 and Tgfβ1) (165)(166)(167). Mice were injected with AOM one week prior to the first round of DSS exposure.…”

“…5.3 Other cytokines essential to the inhibition of tumor growth were also altered by CTBp administration. For example, IFNγ, IL-2 and GM-CSF have been shown to suppress colon cancer progression (165,166,174,175) and the two former cytokines were significantly induced while the latter was reduced by…”