Dataset Information

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

ABSTRACT:

Aims

The BRAF^V600E 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 BRAF^V600E, is not always efficient in resistant tumors suggesting that other compensatory mechanisms contribute to a BRAF^V600E adaptive resistance. Recent studies pointed to a key role of transforming growth factor ? (TGF-?) in BRAF^V600E-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-? in cancer, suggestive of a potential role in BRAF^V600E-induced thyroid tumors.

Results

Here, using two human BRAF^V600E-mutated thyroid cell lines and a rat thyroid cell line expressing BRAF^V600E in a conditional manner, we show that NOX4 upregulation is controlled at the transcriptional level by the oncogene via the TGF-?/Smad3 signaling pathway. Importantly, treatment of cells with NOX4-targeted siRNA downregulates BRAF^V600E-induced NIS repression. Innovation and Conclusion: Our results establish a link between BRAF^V600E 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 BRAF^V600E-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.

SUBMITTER: Azouzi N

PROVIDER: S-EPMC5444494 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Azouzi Naïma N Cailloux Jérémy J Cazarin Juliana M JM Knauf Jeffrey A JA Cracchiolo Jennifer J Al Ghuzlan Abir A Hartl Dana D Polak Michel M Carré Aurore A El Mzibri Mohammed M Filali-Maltouf Abdelkarim A Al Bouzidi Abderrahmane A Schlumberger Martin M Fagin James A JA Ameziane-El-Hassani Rabii R Dupuy Corinne C

Antioxidants & redox signaling 20160822 15

<h4>Aims</h4>The BRAF<sup>V600E</sup> 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 BRAF<sup>V600E</sup>, is not always efficient in resistant tumors suggesting that other compensatory ...[more]

PMID: 27401113

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Project description:BackgroundOver the past ten years, the incidence rate of papillary thyroid carcinoma (PTC) worldwide has been increasing rapidly year by year, with the incidence rate increasing 6% annually. PTC has become the malignant tumor with the highest growth rate in the world that fourteen PTC-related mutant genes have been identified. Whether the BRAFV600E mutation related to more aggressive clinicopathologic features and worse outcome in PTC remains variable and controversial. We aim to investigate the risk factors that may predict the BRAFV600E mutation potential of these lesions and new prevention strategies in PTC patients.MethodsA total of 9,908 papillary thyroid carcinoma patients with average 74.6% BRAFV600E mutations were analyzed (RevMan 5.3 software) in this study. The PubMed, Embase, and ISI Web of Science databases were systematically searched for works published through December 15, 2021.ResultsThe following variables were associated with an increased risk of BRAFV600E mutation in PTC patients: age ≥ 45 years (OR = 1.39, 95%CI = 1.21-1.60, p < 0.00001), male gender (OR = 1.13, 95%CI = 0.99-1.28, p = 0.06), multifocality (OR = 1.22, 95%CI = 1.07-1.40, p = 0.004), lymph node metastasis (OR = 1.33, 95%CI = 0.79-2.23, p = 0.28), extrathyroidal extension + (OR = 1.61, 95%CI = 1.06-2.44, p = 0.03), vascular invasion + (OR = 2.04, 95%CI = 1.32-3.15, p = 0.001), and tumor node metastasis stage (OR = 1.61, 95%CI = 1.38-1.88, p < 0.00001). In addition, tumor size (>1 cm) (OR = 0.51, 95%CI = 0.32-0.81, p = 0.005) and distant metastasis (OR = 0.69, 95%CI = 0.22-2.21, p = 0.54) had no association or risk with BRAFV600E mutation in PTC patients.ConclusionOur systematic review identified the following significant risk factors of BRAFV600E mutation in PTC patients: age (≥45 years), gender (male), multifocality, lymph node metastasis, vascular invasion, extrathyroidal extension, and advanced tumor node metastasis stage (stages III and IV). Tumor size (>1 cm) and distant metastasis do not appear to be correlated with BRAFV600E mutation in PTC patients.

Project description:Background: BRAFV600E acts as an ATP-dependent cytosolic kinase. BRAFV600E inhibitors are widely available, but resistance to them is widely reported in the clinic. Lipid metabolism (fatty acids) is fundamental for energy and to control cell stress. Whether and how BRAFV600E impacts lipid metabolism regulation in papillary thyroid carcinoma (PTC) is still unknown. Acetyl-CoA carboxylase (ACC) is a rate-limiting enzyme for de novo lipid synthesis and inhibition of fatty acid oxidation (FAO). ACC1 and ACC2 genes encode distinct isoforms of ACC. The aim of our study was to determine the relationship between BRAFV600E and ACC in PTC. Methods: We performed RNA-seq and DNA copy number analyses in PTC and normal thyroid (NT) in The Cancer Genome Atlas samples. Validations were performed by using assays on PTC-derived cell lines of differing BRAF status and a xenograft mouse model derived from a heterozygous BRAFWT/V600E PTC-derived cell line with knockdown (sh) of ACC1 or ACC2. Results:ACC2 mRNA expression was significantly downregulated in BRAFV600E-PTC vs. BRAFWT-PTC or NT clinical samples. ACC2 protein levels were downregulated in BRAFV600E-PTC cell lines vs. the BRAFWT/WT PTC cell line. Vemurafenib increased ACC2 (and to a lesser extent ACC1) mRNA levels in PTC-derived cell lines in a BRAFV600E allelic dose-dependent manner. BRAFV600E inhibition increased de novo lipid synthesis rates, and decreased FAO due to oxygen consumption rate (OCR), and extracellular acidification rate (ECAR), after addition of palmitate. Only shACC2 significantly increased OCR rates due to FAO, while it decreased ECAR in BRAFV600E PTC-derived cells vs. controls. BRAFV600E inhibition synergized with shACC2 to increase intracellular reactive oxygen species production, leading to increased cell proliferation and, ultimately, vemurafenib resistance. Mice implanted with a BRAFWT/V600E PTC-derived cell line with shACC2 showed significantly increased tumor growth after vemurafenib treatment, while vehicle-treated controls, or shGFP control cells treated with vemurafenib showed stable tumor growth. Conclusions: These findings suggest a potential link between BRAFV600E and lipid metabolism regulation in PTC. BRAFV600E downregulates ACC2 levels, which deregulates de novo lipid synthesis, FAO due to OCR, and ECAR rates. ShACC2 may contribute to vemurafenib resistance and increased tumor growth. ACC2 rescue may represent a novel molecular strategy for overcoming resistance to BRAFV600E inhibitors in refractory PTC.

Dataset Information

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

Aims

Results

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

NADPH Oxidase NOX4 Is a Critical Mediator of BRAFV600E-Induced Downregulation of the Sodium/Iodide Symporter in Papillary Thyroid Carcinomas.

Aims

Results

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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