title: 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 noncoding 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 that targeted NR3C2 and suppressed its expression. PDAC tumors expressing high levels of MIF displayed elevated levels of miR-301b and reduced levels of NR3C2. In addition, 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. Cancer Res; 76(13); 3838-50. ©2016 AACR.
authors.affiliation: Pancreatic Cancer Unit, National Cancer Institute, Bethesda, Maryland. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Shouhui
authors.initials: S
authors.lastname: Yang
authors.affiliation: Pancreatic Cancer Unit, National Cancer Institute, Bethesda, Maryland. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Peijun
authors.initials: P
authors.lastname: He
authors.affiliation: Pancreatic Cancer Unit, National Cancer Institute, Bethesda, Maryland. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Aaron
authors.initials: A
authors.lastname: Schetter
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Surgery, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Naotake
authors.initials: N
authors.lastname: Funamizu
authors.affiliation: Department of Surgery, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanaga
authors.affiliation: Department of Surgery, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Uwagawa
authors.affiliation: Department Pathology and Microbiology, Ohio State University, Columbus, Ohio.
authors.forename: Abhay R
authors.initials: AR
authors.lastname: Satoskar
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medicine, Göttingen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Gaedcke
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medicine, Göttingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Bernhardt
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medicine, Göttingen, Germany.
authors.forename: B Michael
authors.initials: BM
authors.lastname: Ghadimi
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Gaida
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bergmann
authors.affiliation: Department of Surgery, Ludwig-Maximillians University, Munich, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Werner
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.affiliation: Division of Surgical Oncology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Nader
authors.initials: N
authors.lastname: Hanna
authors.affiliation: Division of Surgical Oncology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: H Richard
authors.initials: HR
authors.lastname: Alexander
authors.affiliation: Pancreatic Cancer Unit, National Cancer Institute, Bethesda, Maryland. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. hussainp@mail.nih.gov.
authors.forename: S Perwez
authors.initials: SP
authors.lastname: Hussain
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D008263:Macrophage Migration-Inhibitory Factors; D035683:MicroRNAs; C561839:NR3C2 protein, human; D018161:Receptors, Mineralocorticoid; D003841:Deoxycytidine; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human; D000093542:Gemcitabine