Urocortin suppresses endometrial cancer cell migration via CRFR2 and its system components are differentially modulated by estrogen

Abstract

Urocortin (UCN1) peptide shares structural and functional homology with corticotropin-releasing factor (CRF). UCN1 is significantly reduced in endometrial adenocarcinoma compared to healthy controls. However, there are no data which evaluate the effects of UCN1 in the endometrium, or how it is modulated. We used proliferation and transwell assays to determine the effect of UCN1 on the proliferation and migration of Ishikawa and HEC1A cells. We also determined the expression levels of UCN1 and its receptors produced by estrogen receptor agonists, and the effect of UCN1 on estrogen receptor expression, using quantitative polymerase chain reaction. UCN1 suppressed migration of endometrial cancer cells in vitro. This effect appears to be specific to CRF receptor 2 (CRFR2), as selective antagonism of CRFR2 but not CRFR1 completely eliminated suppression of migration. Activation of ERA reduced UCN1 expression, but only had a small effect on the expression of CRFR1. However, expression of CRFR2 was more notably reduced at both the mRNA and protein levels by activation of ERB. UCN1 in turn reduced both ERA and ERB expression, as assessed by real-time quantitative PCR. We demonstrate that UCN1 significantly suppresses the migration of endometrial cancer cells but has no effect on their proliferation. Thus, loss of UCN1 in endometrial cancer may promote invasion and metastatic spread. There is a complex relationship between the UCN1 system and estrogen receptors, which may provide insights into endometrial carcinogenesis, a disease known to be driven by estrogen excess. Cancer Medicine Open Access 409

Involvement of Corticotropin-releasing Hormone-related Peptides in Cellular Stress Caused by Anticancer Drugs in Colorectal Cancer

“…It has been reported that these peptides and receptors may influence the proliferation, migration, and invasion potencies of cancer cells (18,19,(32)(33)(34)(35). However, different results have been shown and no consensus has yet been reached.…”

Prognostic Model of Colorectal Cancer Constructed by Eight Immune-Related Genes

“…Urocortin (UCN) is mainly expressed in reproductive organs or urinary systems such as endometrium, testes, epididymis, and urothelial. UCN is a member of the CRH family, and it can inhibit the invasion and metastatic spread of endometrial cancer (Owens et al, 2017). Interleukin-1 receptor-like 2 (IL1RL2), also known as IL-36 receptor, distributed in the intestine, kidney, skin, and brain, is produced by monocytes and T/B lymphocytes.…”

The roles of estrogen receptor alpha (ERα) in endometrial carcinoma

“…In addition to proliferation, the downstream protein FTO also enhances the invasion through PI3K/AKT/mTOR and MAPK signaling pathways [54]. Besides the above substrates, ERα also inhibits epidermal growth factor-containing bulin-like extracellular matrix protein 1 (EFEMP1), retinoblastoma protein-interacting zinc nger gene 1(RIZ1) and urocortin to promote metastasis [55][56][57]. E2/ERα signaling pathway down-regulates EFEMP1 expression by binding to EFEMP1 promoter [55].…”