Abstract
Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy. Aberrant macrophage migration inhibitory factor (MIF) expression is associated with disease aggressiveness and increased MIF in PDAC predicts poor patient survival. Here we show that MIF-induced disease aggressiveness and poor survival in PDAC involves the inhibition of the nuclear receptor subfamily group c member 2 (NR3C2). Tumors with aberrant high levels of MIF (MIF-high) showed an increased expression of mir-301b and a decrease in NR3C2 expression as compared to the tumors with a lower level of MIF (MIF-low) in PDAC cases and a negative correlation existed between MIF and NR3C2 expressions in these tumors. Furthermore, patients with an increase in mir-301b or decrease in NR3C2 expression had a significantly shorter survival than other patients. MIF overexpression and knockdown confirmed that MIF up-regulates miR-301b, which then binds to the 3′UTR of NR3C2 and markedly decreases its expression. Moreover, MIF-overexpressing orthotopic tumor xenografts showed an increase in mir-301b and a decrease in NR3C2 expressions. MIF-induced regulation of mir-301b and NR3C2 functionally involved the PI3Kinase/Akt pathway. Examination of the tumor suppressor mechanism of NR3C2 revealed that it inhibits proliferation, colony formation, migration and invasion, and enhances sensitivity to chemotherapeutic drug gemcitabine in pancreatic cancer cells. Furthermore, NR3C2 knock down enhanced epithelial-to-mesenchymal transition. These data identify a novel MIF-induced signaling pathway targeting NR3C2, leading to increased disease aggressiveness and poor outcome in PDAC. We identified a MIF-driven signaling pathway that inhibits a previously undescribed tumor suppressor of PDAC, NR3C2, involving miR-301b. The inhibition of NR3C2 enhanced disease aggressiveness and predicted to poor survival, as shown by our survival analysis. Therapies that target the MIF-miR-301b-NR3C2 axis may improve disease outcome in pancreatic cancer. Citation Format: Shouhui Yang, Peijun He, Jian Wang, Aaron Schetter, Wei Tang, Naotake Funamizu, Jochen Gaedcke, Michael Ghadimi, Matthias Gaida, Thomas Ried, Nader Hannah, H. Richard Alexander, S. Perwez Hussain. Macrophage migration inhibitory factor (MIF) and miR-301b interactively enhance disease aggressiveness by targeting NR3C2 (nuclear receptor subfamily group c member 2) in human pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 922. doi:10.1158/1538-7445.AM2015-922
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