A Novel MIF Signaling Pathway Drives the Malignant Character of Pancreatic Cancer by Targeting NR3C2

Abstract

Pancreatic cancers with aberrant expression of macrophage migration inhibitory factor (MIF) are particularly aggressive. To identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression, we analyzed the expression of coding and non-coding genes in high and low MIF-expressing tumors in multiple cohorts of pancreatic ductal adenocarcinoma (PDAC) patients. The key genes and pathways identified were linked to patient survival and were mechanistically, functionally and clinically characterized using cell lines, a genetically engineered mouse model and PDAC patient cohorts. Here we report evidence of a novel MIF-driven signaling pathway that inhibits the orphan nuclear receptor NR3C2, a previously undescribed tumor suppressor that impacts aggressiveness and survival in PDAC. Mechanistically, MIF upregulated miR-301b which targeted NR3C2 and suppressed its expression. PDAC tumors expressing high levels of MIF displayed elevated levels of miR-301b and reduced levels of NR3C2. Additionally, reduced levels of NR3C2 expression correlated with poorer survival in multiple independent cohorts of PDAC patients. Functional analysis showed that NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to the gemcitabine, a chemotherapeutic drug used in PDAC standard of care. Furthermore, genetic deletion of MIF disrupted a MIF-mir-301b-NR3C2 signaling axis, reducing metastasis and prolonging survival in a genetically engineered mouse model of PDAC. Taken together, our results offer a preclinical proof-of-principle for candidate therapies to target a newly described MIF-miR-301b-NR3C2 signaling axis for PDAC management.

Low NR3C2 levels correlate with aggressive features and poor prognosis in non‐distant metastatic clear‐cell renal cell carcinoma

“…In colorectal cancer, some studies have demonstrated that decreased MR expression is associated with increased microvascular density and poor patient survival through the direct inhibition of dysregulated VEGFA expression (Di Fabio et al, ; Tiberio et al, ). Similar results have also been demonstrated in early stage cervical carcinoma (Huang et al, ), pancreatic cancer (Yang et al, ), breast cancer (Nan, Dorgan, & Rebbeck, ), and lung cancer (Jeong et al, ). All of the publications mentioned above illustrate that NR3C2 might function as an onco‐suppressor gene in various cancer types.…”

DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth

“…In line with what has been described,13 high cytoplasmic DYRK1B expression was detected in PDAC and PanIN lesions (H-score, n=7: 254.6±21.58) (supplementary figure S1A). DYRK1A mRNA was also increased in PDAC samples as compared with normal adjacent tissue in two inhouse sample sets, and in an independent cohort studied from publicly available microarray data (GSE62452)23 (figure 1B,C). Differential expression of DYRK1B mRNA was only observed in one set of samples (supplementary figure S1B,C).…”

MicroRNA‐766 promotes cancer progression by targeting NR3C2 in hepatocellular carcinoma

“…For instance, overexpression of NR3C2 inhibits cell proliferation, colony formation, invasion, migration, and tubular formation of renal cell carcinoma in vitro and in vivo (15). Yang et al (25) also showed that NR3C2 inhibited epithelial-tomesenchymal transition and cell invasion in pancreatic cancer. In this study, we found that NR3C2 was the target gene of miR-766 and that NR3C2 attenuated miR-766-midiated proliferation, colony formation, invasion, and migration of HCC cells by regulating the b-catenin signaling pathway.…”