Naïma Azouzi1,2,3,4, Jérémy Cailloux1,2,3, Juliana M Cazarin1,2,3,5, Jeffrey A Knauf6, Jennifer Cracchiolo6, Abir Al Ghuzlan1,2,3, Dana Hartl2, Michel Polak7,8,9,10, Aurore Carré7,8, Mohammed El Mzibri4, Abdelkarim Filali-Maltouf11, Abderrahmane Al Bouzidi12, Martin Schlumberger1,2,3, James A Fagin6, Rabii Ameziane-El-Hassani1,2,4, Corinne Dupuy1,2,3. 1. 1 UMR 8200 CNRS , Villejuif, France . 2. 2 Institut Gustave Roussy , Villejuif, France . 3. 3 Université Paris-Saclay , Orsay, France . 4. 4 Unité de Biologie et Recherche Médicale, Centre National de l'Energie , des Sciences et des Techniques Nucléaires, Rabat, Morocco . 5. 5 Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro , Rio de Janeiro, Brazil . 6. 6 Department of Medicine and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center , New York, New York. 7. 7 INSERM U1016 , Paris, France . 8. 8 Imagine Institute , Paris, France . 9. 9 Pediatric Endocrinology, Gynaecology and Diabetology Unit, Hôpital Universitaire Necker-Enfants Malades , AP-HP, Paris, France . 10. 10 Université Paris Descartes-Sorbonne Paris Cité , Paris, France . 11. 11 Laboratoire de Microbiologie et Biologie Moléculaire, Faculté des Sciences, Université Mohammed V , Rabat, Morocco . 12. 12 Equipe de recherche en pathologie tumorale, Faculté de Médecine et de Pharmacie, Université Mohammed V , Rabat, Morocco .
Abstract
AIMS: The BRAFV600E oncogene, 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 BRAFV600E adaptive 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. RESULTS: Here, using two human BRAFV600E-mutated thyroid cell lines and a rat thyroid cell line expressing BRAFV600E in 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 BRAFV600E and 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.
AIMS: The BRAFV600E oncogene, 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 BRAFV600E adaptive 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. RESULTS: Here, using two humanBRAFV600E-mutated thyroid cell lines and a rat thyroid cell line expressing BRAFV600E in 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 BRAFV600E and NOX4, which is confirmed by a comparative analysis of NOX4 expression in human (TCGA) and mousethyroid cancers. Remarkably, analysis of human and murineBRAFV600E-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.
Entities:
Keywords:
BRAFV600E; NADPH oxidase; NIS; NOX4; ROS; papillary thyroid cancer
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