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Bisphenol A at a human exposed level can promote epithelial-mesenchymal transition in papillary thyroid carcinoma harbouring BRAF^V600E mutation.

ABSTRACT: Bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical, alters the function of endocrine system and enhances the susceptibility to tumorigenesis in several hormone-dependent tumours as thyroid carcinoma. About 50% of papillary thyroid cancers (PTC), the most common type of thyroid malignancy, harbours the BRAF^V600E mutation. This study aimed to investigate a potential combined effect of BPA exposure and BRAF^V600E mutation on epithelial-mesenchymal transition (EMT) in PTC. Firstly, the level of BPA in plasma, the evaluation of BRAF^V600E mutation and the level of EMT-related proteins in PTC samples were individually determined. Additionally, the migration, invasion, colony formation capacity and the expression of EMT-related proteins after exposure to BPA were precisely analysed in vitro thyroid cells genetically modified by the introduction of BRAF^V600E mutation. Moreover, ERK-Cox2 signalling pathway was also introduced to explore the possible mechanism in PTC development. As expected, whether the clinical investigation or cultured thyroid cells demonstrated that BPA at a concentration compatible with human exposed levels (10^-7 M) synergized with the BRAF^V600E mutation promoted EMT via the activation of ERK-Cox2 signalling pathway. Our findings offer some evidence that BPA as an environmental risk factor can facilitate the progression of PTC harbouring BRAF^V600E mutation.

SUBMITTER: Li L

PROVIDER: S-EPMC7875916 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Bisphenol A at a human exposed level can promote epithelial-mesenchymal transition in papillary thyroid carcinoma harbouring BRAFV600E mutation.

Li Liuli L Li Hao H Zhang Jun J Gao Xin X Jin Hao H Liu Renqi R Zhang Zhen Z Zhang Xuan X Wang Xichang X Qu Peng P Zhao Yuejiao Y Lu Xiaobo X

Journal of cellular and molecular medicine 20210119 3

Bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical, alters the function of endocrine system and enhances the susceptibility to tumorigenesis in several hormone-dependent tumours as thyroid carcinoma. About 50% of papillary thyroid cancers (PTC), the most common type of thyroid malignancy, harbours the BRAFV600E mutation. This study aimed to investigate a potential combined effect of BPA exposure and BRAFV600E mutation on epithelial-mesenchymal transition (EMT) in ...[more]

PMID: 33469997

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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:BackgroundUltrasound, cytology, and BRAFV600E mutation analysis were applied as valuable tools in the differential diagnosis of thyroid nodules. The aim of the present study was to evaluate the diagnostic efficiency of the three methods and their combined use in screening for papillary thyroid microcarcinoma (PTMC).MethodsA total of 1,081 patients with 1,157 thyroid nodules (0.5-1 cm in maximum diameter) classified as thyroid imaging reporting and data system (TIRADS) 4-5 were recruited. All patients underwent ultrasound, fine-needle aspiration (FNA) examination, and an additional BRAFV600E mutation test. TIRADS and Bethesda System for Reporting Thyroid Cytopathology (BSRTC) were adopted to judge the ultrasound and cytological results. The receiver operating characteristic (ROC) curve was established to assess the diagnostic values of different methods.ResultsOf the 1,157 nodules, 587 were benign and 570 were PTMCs. BRAFV600E mutation test had highest sensitivity (85.4%), specificity (97.1%), accuracy (91.4%), and area under the ROC curve (Az) value (0.913) among the three methods. The combination of BSRTC and BRAFV600E mutation analysis yielded a considerably high sensitivity (96.0%), accuracy (94.3%), and negative predictive value (95.9%) than either BSRTC or BRAFV600E mutation alone (P < 0.0001 for all comparisons). Of all the methods, the combined use of the three methods produced the best diagnostic performance (Az = 0.967), which was significantly higher than that (Az = 0.943) for the combination of BSRTC and BRAFV600E mutation (P < 0.0001). The diagnostic accuracy of the molecular method in the 121 nodules with indeterminate cytology was 90.1% (109/121), which was significantly higher than that of TIRADS classification, 74.4% (90/121) (P = 0.002).ConclusionThe combined use of ultrasound, cytology, and BRAFV600E mutation analysis is the most efficient and objective method for diagnosing PTMC. Both BRAFV600E mutation and TIRADS classification are potentially useful adjuncts to differentiate thyroid nodules, especially indeterminate samples classified as BSRTC III.

Project description:IMPORTANCE:BRAF V600E is a prominent oncogene in papillary thyroid cancer (PTC), but its role in PTC-related patient mortality has not been established. OBJECTIVE:To investigate the relationship between BRAF V600E mutation and PTC-related mortality. DESIGN, SETTING, AND PARTICIPANTS:Retrospective study of 1849 patients (1411 women and 438 men) with a median age of 46 years (interquartile range, 34-58 years) and an overall median follow-up time of 33 months (interquartile range, 13-67 months) after initial treatment at 13 centers in 7 countries between 1978 and 2011. MAIN OUTCOMES AND MEASURES:Patient deaths specifically caused by PTC. RESULTS:Overall, mortality was 5.3% (45/845; 95% CI, 3.9%-7.1%) vs 1.1% (11/1004; 95% CI, 0.5%-2.0%) (P < .001) in BRAF V600E-positive vs mutation-negative patients. Deaths per 1000 person-years in the analysis of all PTC were 12.87 (95% CI, 9.61-17.24) vs 2.52 (95% CI, 1.40-4.55) in BRAF V600E-positive vs mutation-negative patients; the hazard ratio (HR) was 2.66 (95% CI, 1.30-5.43) after adjustment for age at diagnosis, sex, and medical center. Deaths per 1000 person-years in the analysis of the conventional variant of PTC were 11.80 (95% CI, 8.39-16.60) vs 2.25 (95% CI, 1.01-5.00) in BRAF V600E-positive vs mutation-negative patients; the adjusted HR was 3.53 (95% CI, 1.25-9.98). When lymph node metastasis, extrathyroidal invasion, and distant metastasis were also included in the model, the association of BRAF V600E with mortality for all PTC was no longer significant (HR, 1.21; 95% CI, 0.53-2.76). A higher BRAF V600E-associated patient mortality was also observed in several clinicopathological subcategories, but statistical significance was lost with adjustment for patient age, sex, and medical center. For example, in patients with lymph node metastasis, the deaths per 1000 person-years were 26.26 (95% CI, 19.18-35.94) vs 5.93 (95% CI, 2.96-11.86) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 4.43 [95% CI, 2.06-9.51]; adjusted HR, 1.46 [95% CI, 0.62-3.47]). In patients with distant tumor metastasis, deaths per 1000 person-years were 87.72 (95% CI, 62.68-122.77) vs 32.28 (95% CI, 16.14-64.55) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 2.63 [95% CI, 1.21-5.72]; adjusted HR, 0.84 [95% CI, 0.27-2.62]). CONCLUSIONS AND RELEVANCE:In this retrospective multicenter study, the presence of the BRAF V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC. Because overall mortality in PTC is low and the association was not independent of tumor features, how to use BRAF V600E to manage mortality risk in patients with PTC is unclear. These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC.

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

Bisphenol A at a human exposed level can promote epithelial-mesenchymal transition in papillary thyroid carcinoma harbouring BRAF^V600E mutation.

Publications

Bisphenol A at a human exposed level can promote epithelial-mesenchymal transition in papillary thyroid carcinoma harbouring BRAF<sup>V600E</sup> mutation.

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