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 K/K ) mice were used to explore the role of CRHR1 in the development of azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced CAC. WT (Crhr1 C/C ) 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 C/C mice during treatment with AOM and DSS. Tumorigenesis was significantly reduced in Crhr1 K/K 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 K/K mice exhibited much less tumorigenesis, accompanied by lower inflammatory response, including decreased IL1b, IL6 and TNFa expression and macrophage infiltration and increased IL10 expression. Moreover, Crhr1 K/K mice displayed a reduced activation of NFkB 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.

Hypermethylation of Corticotropin Releasing Hormone Receptor-2 Gene in Ulcerative Colitis Associated Colorectal Cancer

“…Chatzaki, et al have reported that CRHR2 expression in the colonic epithelial cells was down-regulated both in patients with moderately active UC and those in remission (37). CRHR1 has a pro-inflammatory and therefore a pro-tumorigenesis effect in terms of colitis associated cancer (38). Inhibition of the expression of CRHR2 correlates with tumor expansion, epithelial-mesenchymal transition, distant metastasis risk and poor survival in experimental CRC models and in CRC patients (39).…”

Increased accuracy of a novel mRNA‐based urine test for bladder cancer surveillance

“…The corticotropin‐releasing hormone (CRH) system was initially identified as a hypothalamus‐directed mediator of neuroendocrine stress response, while recent studies suggest a link between CRH and the development of solid cancers . Preclinical studies showed the proinflammatory and procarcinogenic nature of CRH family peptides and their receptors, and the fact that they modulate immunity, inflammation and tumour cell growth .…”

Corticotropin-releasing hormone improves survival in pneumococcal pneumonia by reducing pulmonary inflammation

“…; Liu et al. ). To date, few studies have defined the role of CRH in the regulation of pulmonary cellular immune and inflammatory responses (O'Kane et al.…”

“…Its ability to influence immune function is commonly associated with the release of adrenal corticotropic hormone (ACTH) from the adrenal glands, resulting in cortisol release that in turn translates into nonspecific immune suppression (Rodgers and Klugman 2011). Alternatively, CRH is also secreted in peripheral tissues (e.g., synovial tissue, gastrointestinal tract, placenta), where it is believed to modulate cellular immune and inflammatory responses through preferences in CRH receptors 1 and 2 activity (Peracoli et al 2011;Zhu et al 2011;Liu et al 2014). To date, few studies have defined the role of CRH in the regulation of pulmonary cellular immune and inflammatory responses (O'Kane et al 2006).…”