title: NADPH Oxidase NOX4 Is a Critical Mediator of BRAFV600E-Induced Downregulation of the Sodium/Iodide Symporter in Papillary Thyroid Carcinomas.
abstract: The BRAFV600Eoncogene, reported in 40%-60% of papillary thyroid cancer (PTC), has an important role in the pathogenesis of PTC. It is associated with the loss of thyroid iodide-metabolizing genes, such as sodium/iodide symporter (NIS), and therefore with radioiodine refractoriness. Inhibition of mitogen-activated protein kinase (MAPK) pathway, constitutively activated by BRAFV600E, is not always efficient in resistant tumors suggesting that other compensatory mechanisms contribute to a BRAFV600Eadaptive resistance. Recent studies pointed to a key role of transforming growth factor β (TGF-β) in BRAFV600E-induced effects. The reactive oxygen species (ROS)-generating NADPH oxidase NOX4, which is increased in PTC, has been identified as a new key effector of TGF-β in cancer, suggestive of a potential role in BRAFV600E-induced thyroid tumors.
  
  
  
  Here, using two human BRAFV600E-mutated thyroid cell lines and a rat thyroid cell line expressing BRAFV600Ein a conditional manner, we show that NOX4 upregulation is controlled at the transcriptional level by the oncogene via the TGF-β/Smad3 signaling pathway. Importantly, treatment of cells with NOX4-targeted siRNA downregulates BRAFV600E-induced NIS repression. Innovation and Conclusion: Our results establish a link between BRAFV600Eand NOX4, which is confirmed by a comparative analysis of NOX4 expression in human (TCGA) and mouse thyroid cancers. Remarkably, analysis of human and murine BRAFV600E-mutated thyroid tumors highlights that the level of NOX4 expression is inversely correlated to thyroid differentiation suggesting that other genes involved in thyroid differentiation in addition to NIS might be silenced by a mechanism controlled by NOX4-derived ROS. This study opens a new opportunity to optimize thyroid cancer therapy. Antioxid. Redox Signal. 26, 864-877.
authors.affiliation: 1 UMR 8200 CNRS , Villejuif, France .|2 Institut Gustave Roussy , Villejuif, France .|3 Université Paris-Saclay , Orsay, France .|4 Unité de Biologie et Recherche Médicale, Centre National de l'Energie , des Sciences et des Techniques Nucléaires, Rabat, Morocco .
authors.forename: Naïma
authors.initials: N
authors.lastname: Azouzi
authors.affiliation: 1 UMR 8200 CNRS , Villejuif, France .|2 Institut Gustave Roussy , Villejuif, France .|3 Université Paris-Saclay , Orsay, France .
authors.forename: Jérémy
authors.initials: J
authors.lastname: Cailloux
authors.affiliation: 1 UMR 8200 CNRS , Villejuif, France .|2 Institut Gustave Roussy , Villejuif, France .|3 Université Paris-Saclay , Orsay, France .|5 Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil .
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Cazarin
authors.affiliation: 6 Department of Medicine and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center , New York, New York.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Knauf
authors.affiliation: 6 Department of Medicine and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center , New York, New York.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cracchiolo
authors.affiliation: 1 UMR 8200 CNRS , Villejuif, France .|2 Institut Gustave Roussy , Villejuif, France .|3 Université Paris-Saclay , Orsay, France .
authors.forename: Abir
authors.initials: A
authors.lastname: Al Ghuzlan
authors.affiliation: 2 Institut Gustave Roussy , Villejuif, France .
authors.forename: Dana
authors.initials: D
authors.lastname: Hartl
authors.affiliation: 7 INSERM U1016 , Paris, France .|8 Imagine Institute , Paris, France .|9 Pediatric Endocrinology, Gynaecology and Diabetology Unit, Hôpital Universitaire Necker-Enfants Malades , AP-HP, Paris, France .|10 Université Paris Descartes-Sorbonne Paris Cité , Paris, France .
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
authors.affiliation: 7 INSERM U1016 , Paris, France .|8 Imagine Institute , Paris, France .
authors.forename: Aurore
authors.initials: A
authors.lastname: Carré
authors.affiliation: 4 Unité de Biologie et Recherche Médicale, Centre National de l'Energie , des Sciences et des Techniques Nucléaires, Rabat, Morocco .
authors.forename: Mohammed
authors.initials: M
authors.lastname: El Mzibri
authors.affiliation: 11 Laboratoire de Microbiologie et Biologie Moléculaire, Faculté des Sciences, Université Mohammed V , Rabat, Morocco .
authors.forename: Abdelkarim
authors.initials: A
authors.lastname: Filali-Maltouf
authors.affiliation: 12 Equipe de recherche en pathologie tumorale, Faculté de Médecine et de Pharmacie, Université Mohammed V , Rabat, Morocco .
authors.forename: Abderrahmane
authors.initials: A
authors.lastname: Al Bouzidi
authors.affiliation: 1 UMR 8200 CNRS , Villejuif, France .|2 Institut Gustave Roussy , Villejuif, France .|3 Université Paris-Saclay , Orsay, France .
authors.forename: Martin
authors.initials: M
authors.lastname: Schlumberger
authors.affiliation: 6 Department of Medicine and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center , New York, New York.
authors.forename: James A
authors.initials: JA
authors.lastname: Fagin
authors.affiliation: 1 UMR 8200 CNRS , Villejuif, France .|2 Institut Gustave Roussy , Villejuif, France .|4 Unité de Biologie et Recherche Médicale, Centre National de l'Energie , des Sciences et des Techniques Nucléaires, Rabat, Morocco .
authors.forename: Rabii
authors.initials: R
authors.lastname: Ameziane-El-Hassani
authors.affiliation: 1 UMR 8200 CNRS , Villejuif, France .|2 Institut Gustave Roussy , Villejuif, France .|3 Université Paris-Saclay , Orsay, France .
authors.forename: Corinne
authors.initials: C
authors.lastname: Dupuy
mesh_terms: D000818:Animals; D002291:Carcinoma, Papillary / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D000074663:NADPH Oxidase 4 / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D027981:Symporters / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000099209:Sodium-Iodide Symporters
chemical_list: D000074663:NADPH Oxidase 4; D048493:Proto-Oncogene Proteins B-raf; D012333:RNA, Messenger; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C498910:NOX4 protein, human; C482119:BRAF protein, human
keywords: BRAFV600E; NADPH oxidase; NIS; NOX4; ROS; papillary thyroid cancer