title: The Mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and Epithelial Mesenchymal Transition (EMT) in human lung cancer.
abstract: Recent epidemiologic studies implying differences in cancer recurrence based on anesthetic regimens raise the possibility that the mu opioid receptor (MOR) can influence cancer progression. Based on our previous observations that overexpression of MOR in human non-small cell lung cancer (NSCLC) cells increased tumor growth and metastasis, this study examined whether MOR regulates growth factor receptor signaling and epithelial mesenchymal transition (EMT) in human NSCLC cells. We utilized specific siRNA, shRNA, chemical inhibitors and overexpression vectors in human H358 NSCLC cells that were either untreated or treated with various concentrations of DAMGO, morphine, fentanyl, EGF or IGF. Cell function assays, immunoblot and immunoprecipitation assays were then performed. Our results indicate MOR regulates opioid and growth factor-induced EGF receptor signaling (Src, Gab-1, PI3K, Akt and STAT3 activation) which is crucial for consequent human NSCLC cell proliferation and migration. In addition, human NSCLC cells treated with opioids, growth factors or MOR overexpression exhibited an increase in snail, slug and vimentin and decrease ZO-1 and claudin-1 protein levels, results consistent with an EMT phenotype. Further, these effects were reversed with silencing (shRNA) or chemical inhibition of MOR, Src, Gab-1, PI3K, Akt and STAT3 (p<0.05). Our data suggest a possible direct effect of MOR on opioid and growth factor-signaling and consequent proliferation, migration and EMT transition during lung cancer progression. Such an effect provides a plausible explanation for the epidemiologic findings.
authors.affiliation: Section of Pulmonary and Critical Care, Department of Medicine, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lennon
authors.affiliation: Section of Pulmonary and Critical Care, Department of Medicine, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Tamara
authors.initials: T
authors.lastname: Mirzapoiazova
authors.affiliation: Section of Pulmonary and Critical Care, Department of Medicine, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Bolot
authors.initials: B
authors.lastname: Mambetsariev
authors.affiliation: Department of Surgery, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Valeriy A
authors.initials: VA
authors.lastname: Poroyko
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.affiliation: Department of Anesthesia and Critical Care, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Moss
authors.affiliation: Section of Pulmonary and Critical Care, Department of Medicine, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, United States of America; Department of Anesthesia and Critical Care, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Singleton
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000777:Anesthetics / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D000777:Anesthetics; D017450:Receptors, Opioid, mu; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors