CRHR2/Ucn2 signaling is a novel regulator of miR‐7/YY1/Fas circuitry contributing to reversal of colorectal cancer cell resistance to Fas‐mediated apoptosis

Abstract

Colorectal cancer (CRC) responds poorly to immuno-mediated cytotoxicity. Underexpression of corticotropin-releasing-hormone-receptor-2 (CRHR2) in CRC, promotes tumor survival, growth and Epithelial to Mesenchymal Transition (EMT), in vitro and in vivo. We explored the role of CRHR2 downregulation in CRC cell resistance to Fas/FasL-mediated apoptosis and the underlying molecular mechanism. CRC cell sensitivity to CH11-induced apoptosis was compared between Urocortin-2 (Ucn2)-stimulated parental and CRHR2-overexpressing CRC cell lines and targets of CRHR2/Ucn2 signaling were identified through in vitro and ex vivo analyses. Induced CRHR2/Ucn2 signaling in SW620 and DLD1 cells increased specifically their sensitivity to CH11-mediated apoptosis, via Fas mRNA and protein upregulation. CRC compared to control tissues had reduced Fas expression that was associated with lost CRHR2 mRNA, poor tumor differentiation and high risk for distant metastasis. YY1 silencing increased Fas promoter activity in SW620 and re-sensitized them to CH11-apoptosis, thus suggesting YY1 as a putative transcriptional repressor of Fas in CRC. An inverse correlation between Fas and YY1 expression was confirmed in CRC tissue arrays, while elevated YY1 mRNA was clinically relevant with advanced CRC grade and higher risk for distant metastasis. CRHR2/Ucn2 signaling downregulated specifically YY1 expression through miR-7 elevation, while miR-7 modulation in miR-7 SW620-CRHR2+ and miR-7 HCT116 cells, had opposite effects on YY1 and Fas expressions and cell sensitivity to CH11-killing. CRHR2/Ucn2 signaling is a negative regulator of CRC cell resistance to Fas/FasL-apoptosis via targeting the miR-7/YY1/Fas circuitry. CRHR2 restoration might prove effective in managing CRC response to immune-mediated apoptotic stimuli.

WGCNA reveals key gene modules regulated by the combined treatment of colon cancer with PHY906 and CPT11

“…A new research found that ANXA2 mRNA is up-regulated at all stages of colon cancer and ANXA2 protein levels associate with high probability of invasion and distant metastasis [75]. In a previous study, CRHR2 was identified as a gene which contributing to reversal of colorectal cancer cell resistance [76]. Consistent with the result of functional enrichment analysis for the yellowgreen module, the hub genes were also significantly enriched in terms of spliceosome.…”

miR-7 Suppresses Tumor Progression by Directly Targeting MAP3K9 in Pancreatic Cancer

“… 5 Moreover, corticotropin-releasing hormone receptor 2 and urocortin-2 (CRHR2/Ucn2) signaling is involved in negative regulation of the miR-7/YY1/Fas circuitry to increase the sensitivity of colorectal cancer cells to Fas- and FasL-mediated apoptosis. 6 In addition, downregulated expression of miR-7 was observed in glioma samples and correlated with tumor grades. 7 , 8 Furthermore, the methylation status of miR-7 is associated with upregulation of MAF bZIP transcription factor G (MAFG), leading to CDDP (cisplatin) resistance and a worse prognosis in ovarian cancer patients.…”

Development of a prognostic index and screening of potential biomarkers based on immunogenomic landscape analysis of colorectal cancer

“…These findings provide a new perspective to interrogate the prognostic role of differentially expressed immunity genes in CRC through identification of their receptors. Among the 10 immune genes of prognostic value, used to build our model, Fatty Acid Binding Protein 4 (FABP4) [36,37], NGF [38,39], Resistin Like Beta (RETNLB) [40,41], Urocortin (UCN) [42,43], Vasoactive Intestinal Peptide (VIP) [44,45], Nerve Growth Factor Receptor (NGFR) [46,47] have been implicated in direct or indirect involvement in regulation of CRC development and metastasis through other pathways. However, IGKV1-33, IGKV2D-40, IGLV6-57, and OXTR have not been previously associated with CRC.…”