Corticotropin-Releasing Hormone Receptor Alters the Tumor Development and Growth in Apcmin/+ Mice and in a Chemically-Induced Model of Colon Cancer.

Yunna Lee,Marisa Patel,Sang Hoon Rhee,Yong Sung Kim,Eunok Im,Gayoung Kim,Charalabos Pothoulakis,Elise L Ma,Cody Howe

doi:10.3390/ijms22031043

Abstract

The neuroendocrine circuit of the corticotropin-releasing hormone (CRH) family peptides, via their cognate receptors CRHR1 and CRHR2, copes with psychological stress. However, peripheral effects of the CRH system in colon cancer remains elusive. Thus, we investigate the role of CRHR1 and CRHR2 in colon cancer. Human colon cancer biopsies were used to measure the mRNA levels of the CRH family by quantitative real-time PCR. Two animal models of colon cancer were used: Apcmin/+ mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice. The mRNA levels of CRHR2 and UCN III are reduced in human colon cancer tissues compared to those of normal tissues. Crhr1 deletion suppresses the tumor development and growth in Apcmin/+ mice, while Crhr2 deficiency exacerbates the tumorigenicity. Crhr1 deficiency not only inhibits the expression of tumor-promoting cyclooxygenase 2, but also upregulates tumor-suppressing phospholipase A2 in Apcmin/+ mice; however, Crhr2 deficiency does not change these expressions. In the AOM/DSS model, Crhr2 deficiency worsens the tumorigenesis. In conclusion, Crhr1 deficiency confers tumor-suppressing effects in Apcmin/+ mice, but Crhr2 deficiency worsens the tumorigenicity in both Apcmin/+ and AOM/DSS-treated mice. Therefore, pharmacological inhibitors of CRHR1 or activators of CRHR2 could be of significance as anti-colon cancer drugs.

Highlights

Corticotropin-releasing hormone (CRH, known as corticotrophin-releasing factor) is a group of hypothalamic peptides that regulates the psychological responses of the hypothalamic-pituitary-adrenal (HPA) axis [1,2]
We found that the mRNA level of Corticotropin-Releasing Hormone Receptor 2 (CRHR2) was substantially lower in colon cancer tissues than that of normal tissues, while the CRH receptor 1 (CRHR1) levels are comparable between these tissues (Figure 1A)
Given the reduced expression of CRHR2 and its ligand UCN III in human colon cancer tissues, these findings indicate that the impairment of CRHR2-mediated responses3sohfo1u6ld be associated with colon cancer development in humans, which may contribute to cancer metastasis or poor patient survival

Summary

Introduction

Corticotropin-releasing hormone (CRH, known as corticotrophin-releasing factor) is a group of hypothalamic peptides that regulates the psychological responses of the hypothalamic-pituitary-adrenal (HPA) axis [1,2]. CRH is secreted from the hypothalamus in response to stress, and subsequently induces the production of stress hormones such as glucocorticoids and adrenocorticotropin [3]. CRH-induced glucocorticoids mitigate the stress response by suppressing the endocrine activity of the hypothalamus and the pituitary gland [4]. Given the ability of glucocorticoids to suppress inflammation and immune responses, the CRH family peptides regulate the inflammation and immune responses at peripheral organs [5,6]. It is generally accepted that CRHR1 copes with stress responses of the HPA axis by inducing adrenal corticotropic hormone [11]. CRHR2 is involved in regulating various cellular events, including mucosal repair in colitis [13], angiogenesis [14], and Fas-mediated apoptosis in colon cancer [15]

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Conclusion