title: Nrf2-heme oxygenase-1 axis in mucoepidermoid carcinoma of the lung: Antitumoral effects associated with down-regulation of matrix metalloproteinases.
abstract: Lung mucoepidermoid carcinoma (MEC) is a very poorly characterized rare subtype of non-small-cell lung cancer (NSCLC) associated with more favorable prognoses than other forms of intrathoracic malignancies. We have previously identified that heme oxygenase-1 (HO-1, encoded by HMOX1) inhibits MEC tumor growth and modulates the transcriptome of microRNAs. Here we investigate the role of a major upstream regulator of HO-1 and a master regulator of cellular antioxidant responses, transcription factor Nrf2, in MEC biology. Nrf2 overexpression in the NCI-H292 MEC cell line mimicked the phenotype of HO-1 overexpressing cells, leading to inhibition of cell proliferation and migration and down-regulation of oncogenic miR-378. HMOX1 silencing identified HO-1 as a major mediator of Nrf2 action. Nrf2- and HO-1 overexpressing cells exhibited strongly diminished expression of multiple matrix metalloproteinases and inflammatory cytokine interleukin-1β, which was confirmed in an NCI-HO-1 xenograft model. Overexpression of HO-1 altered not only human MMP levels in tumor cells but also murine MMP levels within tumor microenvironment and metastatic niche. This could possibly contribute to decreased metastasis to the lungs and inhibitory effects of HO-1 on MEC tumor growth. Our profound transcriptome analysis and molecular characterization of the mucoepidermoid lung carcinoma helps to understand the specific clinical presentations of these tumors, emphasizing a unique antitumoral role of the Nrf2-HO-1 axis.
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland; Centre de Biophysique Moleculaire, CNRS UPR 4301, Rue Charles Sadron 45071 Cedex 2 Orléans, France; Department of Molecular Neuropharmacology, Institute of Pharmacology Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Tertil
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland; Department of Molecular Neuropharmacology, Institute of Pharmacology Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland.
authors.forename: Slawomir
authors.initials: S
authors.lastname: Golda
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland; Centre de Biophysique Moleculaire, CNRS UPR 4301, Rue Charles Sadron 45071 Cedex 2 Orléans, France.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Skrzypek
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
authors.forename: Urszula
authors.initials: U
authors.lastname: Florczyk
authors.affiliation: Centre de Biophysique Moleculaire, CNRS UPR 4301, Rue Charles Sadron 45071 Cedex 2 Orléans, France.
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Weglarczyk
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Kotlinowski
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Maleszewska
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
authors.forename: Szymon
authors.initials: S
authors.lastname: Czauderna
authors.affiliation: Centre de Biophysique Moleculaire, CNRS UPR 4301, Rue Charles Sadron 45071 Cedex 2 Orléans, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Pichon
authors.affiliation: Centre de Biophysique Moleculaire, CNRS UPR 4301, Rue Charles Sadron 45071 Cedex 2 Orléans, France; Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland.
authors.forename: Claudine
authors.initials: C
authors.lastname: Kieda
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Jozkowicz
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland; Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland. Electronic address: jozef.dulak@uj.edu.pl.
authors.forename: Jozef
authors.initials: J
authors.lastname: Dulak
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D018277:Carcinoma, Mucoepidermoid / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D049109:Cell Proliferation; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D051547:Heme Oxygenase-1; D020782:Matrix Metalloproteinases
keywords: Heme oxygenase-1; MMP-1; Matrix metalloproteinases; Mucoepidermoid carcinoma; Non-small cell lung cancer; Nrf2; Nuclear factor (erythroid-derived 2)-like 2