The role of corticotropin-releasing hormone receptor 1 in the development of colitis-associated cancer in mouse model.

ABSTRACT

Patients with ulcerative colitis are at a very high risk of developing colorectal cancer. Corticotrophin-releasing hormone (CRH) family peptides and their receptors (CRHRs) are found to modulate inflammation and tumor cell growth. However, the role of CRH family peptides and their receptors in the inflammation-related colon cancer is still unknown. The aim of this study was to investigate the functions of CRHR1 signaling on the development of colitis-associated cancer (CAC). Crhr1-deficient (Crhr1(-/-)) mice were used to explore the role of CRHR1 in the development of azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced CAC. WT (Crhr1(+/+)) littermates were set as control. We found that the expression of CRHR1 and its endogenous ligands urocortin and CRH were enhanced in the colon of Crhr1(+/+) mice during treatment with AOM and DSS. Tumorigenesis was significantly reduced in Crhr1(-/-) mice, determined by analysis of survival rate (increased by 20%), weight loss (decreased by 10%), tumor formation (decreased by 60% in tumor number), histological scores (decreased by 58%), and cytokine production. During early CAC tumorigenesis, Crhr1(-/-) mice exhibited much less tumorigenesis, accompanied by lower inflammatory response, including decreased IL1ß, IL6 and TNFα expression and macrophage infiltration and increased IL10 expression. Moreover, Crhr1(-/-) mice displayed a reduced activation of NFκB and STAT3 phosphorylation with decreased proliferating and enhanced apoptotic cells in the colon. In conclusion, CRHR1 has a proinflammatory and therefore a protumorigenesis effect in terms of CAC, which may be helpful to develop new therapeutic approaches for inflammation and cancer prevention and treatment.