NADPH Oxidase NOX4 Is a Critical Mediator of BRAF V600E -Induced Downregulation of the Sodium/Iodide Symporter in Papillary Thyroid Carcinomas

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Abstract
Aims: The BRAFV600E oncogene, reported in 40-60% of papillary thyroid carcinoma (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 radioiodide-refractoriness. Inhibition of 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 TGF-β in BRAFV600E-induced effects. The reactive oxygene 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 up-regulation 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

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