Deficiency of interferon-gamma or its receptor promotes colorectal cancer development.
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.
1 Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University , Jinan, China .
Lu
L
Wang
Yan
Y
Wang
Zhiyu
Z
Song
Jiahui
J
Chu
Xianjun
X
Qu
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics*; D055785:Gene Knockdown Techniques; D014644:Genetic Variation; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007371:Interferon-gamma / Q000097:blood / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D017471:Receptors, Interferon / Q000172:deficiency* / Q000235:genetics; D012307:Risk Factors; D000096743:Interferon gamma Receptor
D000998:Antiviral Agents; D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor