Thèses sur le sujet « Cancer papillaire de la thyroïde (PTC) »
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Azouzi, Naima. « Etude de l’implication de la NADPH oxydase NOX4 et du stress oxydatif dans la radiorésistance des cancers papillaires de la thyroïde exprimant l’oncogène BRAFV600E ». Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS416.
Texte intégralOne of the major properties of the thyroid is iodine uptake from the bloodstream through an iodide transporter (NIS for Natrium Iodide Symporter). This capacity plays a key role in the thyroid hormones synthesis, but also in both diagnosis and treatment of thyroid cancer. However, due to a decrease or absence of the NIS expression in some tumors and metastases, patients become refractory to the metabolic radiotherapy and present a radioresistance, which cause a public health problem.The BRAFV600E oncogene, a potent activator of the MAP kinase pathway, is detected in 40-60% of papillary thyroid cancer (PTC), which represent 80% of total thyroid cancers. The BRAFV600E mutation is associated with the more aggressive thyroid tumors. However, the pharmacological inhibition of the MAP kinase pathway, constitutively induced by the BRAFV600E oncogene, is not able to restore alone the expression of NIS in patients with BRAFV600E mutated thyroid cancer. This suggests that other compensatory mechanisms may contribute to the radioresistance. A recent study in a mouse model demonstrated that downregulation of NIS by BRAFV600E oncogene is mediated through the TGF beta activation. An other showed that the expression of NIS is dependent on the redox status of the cell, suggesting a role for the reactive oxygen species (ROS). In cells, ROS can be produced by the NADPH oxidases (NOX/DUOX). The Thyroid gland expresses three of them: DUOX2, which is necessary for the thyroid hormones synthesis, but also DUOX1 and NOX4 whose the physiological role remains unknown. NOX4, which is overexpressed in the PTCs, has been shown to be a new key effector of the TGF beta pathway.In my thesis project, I was interested in studying the role of NOX4 in the negative regulation of NIS in BRAFV600E mutated CPT. The study of the mechanism, made from two human cell lines derived from BRAF-mutated papillary thyroid cancers (BCPAP and 8505C), has revealed that the oncogene BRAFV600E controls the expression of NOX4 at the transcriptional level via the TGF-beta/Smad3 pathway. These results were validated on both a rat thyroid cell line conditionnaly expressing BRAFV600E and on human thyrocytes in primary culture. Importantly, the use of antioxidants such as N-acetyl cysteine (NAC) or specific inhibition of NOX4 expression by RNA interference allow reinduction of NIS expression. These results, which show that ROS produced by NOX4 inhibit the expression of iodine transporter (NIS), establish a link between the oncogene BRAFV600E and NOX4. A comparative analysis of the NOX4 expression, made from 500 papillary thyroid cancers mutated or not for BRAF (TCGA data), confirms that NOX4 is significantly increased in BRAF-mutated cancers and that this is correlated with a decrease of NIS mRNA. Furthermore, the level of NOX4 is inversely related to thyroid differentiation score, suggesting that NOX4 might be involved in the dedifferentiation process. This study opens a new opportunity for optimizing the use of metabolic radiotherapy in the treatment of thyroid cancers refractory to radioiodine I131and makes NOX4 as a potential therapeutic target
Fenniche, Salma. « Rôle de la NADPH OXYDASE NOX4 dans la régulation de l'expression et de l'activité de CHD4 dans les tumeurs thyroïdiennes porteuses de la mutation BRAFV600E ». Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASL022.
Texte intégralMetabolic radiotherapy with radioiodine is the cornerstone of the treatment of distant metastases of differentiated thyroid cancers. This therapy depends on the expression at the basal membrane of thyrocytes of the Natrium Iodide Symporter 'NIS'. BRAFV600E mutation is present in 45 to 60% of papillary thyroid carcinomas, which represent 80% of thyroid cancers. The presence of this mutation is associated with the most aggressive thyroid tumors with low levels or absence of NIS expression. The loss of radioactive iodine uptake translates into resistance to metabolic radiotherapy, constituting a major issue for the treatment of patients with this cancer. One approach for treating patients refractory to metabolic radiotherapy is to increase iodine uptake.At the transcriptional level, our team has already shown, through a comparative analysis concerning approximately 500 PTCs from the TCGA database, that NOX4 was strongly expressed in PTCs-BRAFV600E compared to PTCs-BRAFwt. However, at the protein level, no link has been established between the BRAFV600E mutation and NOX4 in malignant and non-malignant tumors (BRAFV600E/BRAFwt). In my thesis project, we illustrate for the first time a positive correlation between the presence of BRAFV600E mutation and the overexpression of NOX4 protein in PTC tumor tissues. The overexpression of NOX4 was associated with an aggressive nature of tumors. Furthermore, we showed that 60% of infiltrating C-PTCs overexpress NOX4 independently of BRAF mutational status, suggesting that NOX4 could be considered as a potential co-marker of PTC aggressiveness. Interestingly, NOX4 protein was also overexpressed in non-malignant thyroid diseases (Basedow, goiters, and hyperplasias), with different subcellular localizations, suggesting a role for NOX4 in progression to thyroid malignancy.Furthermore, on a mechanistic level, our team has previously shown that BRAFV600E controls the expression of NOX4 under the effect of TGF-β/SMAD3 and that NOX4-derived ROS contribute to the repression of NIS. Inhibition of NOX4 promotes reactivation of the NIS. This reversibility suggests a contribution to an epigenetic mechanism. CHD4, a subunit of the NuRD remodeling complex, plays an essential role in gene repression. it was found to be strongly expressed in PTCs, in which it was associated with a poor prognosis. In this study, we showed that the TGF-β/SMAD3 pathway regulates the expression of CHD4 protein. The latter cooperates with DNMTs in repressing NIS in several thyroid tumor cells lines mutated for BRAFV600E. Furthermore, we showed that CHD4 responds to oxidative DNA damage induced by NOX4-derived ROS. Indeed, inhibition of NOX4 or its functional partner p22phox reduces the recruitment of CHD4 to chromatin. This recruitment depends on OGG1 and MSH6, two proteins involved in oxidative DNA damage repair. This study identifies CHD4 as a new therapeutic candidate in radioiodine-refractory thyroid cancers
Ali, Hafiz Muhammad. « Effects of siRNA-squalene nanoparticles on RET/PTCs junction oncogenes in papillary thyroid carcinoma : from molecular and cellular studies to preclinical investigations ». Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T016/document.
Texte intégralPapillary thyroid carcinoma (PTC) is the most common of thyroid cancers. PTC is characterized by chromosomal rearrangements affecting chromosome 10 and leading to RET/PTC junction oncogenes. The most frequent ones are RET/PTC1 and RET/PTC3. Because the junction oncogenes are present only in the tumour cells, they represent a good target for a specific therapy such as small interfering RNA (siRNA). Our aim is to introduce a new pharmacological approach by siRNA for PTC. To perform the experiments, human BHP10-3 SCmice cell line expressing RET/PTC1 was used. Due to absence of commercially available RET/PTC3 cell line, we established a new RP3 cell line (from NIH/3T3 mouse fibroblasts, transfected stably with the RET/PTC3 expression vector) which was found to become tumorigenic in nude mice. siRNAs were designed within the junction sequences of both RET/PTC1 and RET/PTC3. Both siRNAs were found efficient and specific against their own junction oncogenes and were not able to inhibit the expression of alternate sequences. Then, siRNAs were vectorized in the form of nanoparticles (NPs) of squalene (SQ). In vitro, both siRNA RET/PTC1-SQ NPs and siRNA RET/PTC3-SQ NPs were found to be inefficient in gene and protein inhibitions except once transfected with lipofectamine. Therefore, a peptide GALA-Chol was added in siRNA RET/PTC1-SQ NPs which rendered them efficient in vitro in gene and protein inhibitions but found to be inefficient in vivo. The nanoparticles of siRNA RET/PTC1-SQ NPs (0.5 mg/kg/mouse) and siRNA RET/PTC3-SQ NPs (2.5 mg/kg/mouse) were found to drastically reduce the tumor growth and RET/PTCs oncogene and oncoprotein expressions. Moreover, they induced cell death by cleavage of both caspase-3 and PARP-1 and partially restored differentiation (decrease of Ki67 marker). Our findings highly support the use of siRNAs-SQ NPs as a treatment for patients affected by PTC expressing RET/PTCs
Liu, Tingting, et 劉婷婷. « Thyroid transcription factor 1 gene(TITF1) : apotential heritable determinant of papillary thyroid carcinoma(PTC) ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39793898.
Texte intégralKrishnan, Aswini [Verfasser]. « Identification and characterization of novel targets in Papillary Thyroid Cancer (PTC) / Aswini Krishnan ». Mainz : Universitätsbibliothek Mainz, 2019. http://d-nb.info/1195196849/34.
Texte intégralIrani, Soussan. « The Endothelin Axis and Angiogenesis in Papillary Thyroid Carcinoma ». Thesis, Griffith University, 2014. http://hdl.handle.net/10072/366833.
Texte intégralThesis (PhD Doctorate)
School of Medical Science
Griffith Health
Full Text
Paulin, Christian. « Étude du cancer papillaire de la thyroïde : établissement et caractérisation de la lignée B-CPAP ». Lyon 1, 1996. http://www.theses.fr/1996LYO1T072.
Texte intégralBonnin, Christian. « Evolution de 111 microcarcinomes papillaires thyroi͏̈diens : étude rétrospective de 1953 à 1994, expérience de l'Institut Bergonié ». Bordeaux 2, 1996. http://www.theses.fr/1996BOR23091.
Texte intégralSeignovert, Béatrice Coste. « Exploitation d'une enquête internationale sur le diagnostic et le traitement du nodule thyroi͏̈dien et des cancers différenciés de la thyroi͏̈de ». Montpellier 1, 1988. http://www.theses.fr/1988MON11228.
Texte intégralMartinez, Alfaro Minerva. « Réarrangements du proto-oncogène RET dans le cancer papillaire de la thyroi͏̈de : prévalence dans les carcinomes sporadiques (microcarcinomes) et familiaux, et effets des radiations ionisantes sur RET ». Lyon 1, 2002. http://www.theses.fr/2002LYO1T181.
Texte intégralMartimprey, Henri de. « Développement d'une formulation à base de nanoparticules pour la libération de siRNA dans un modèle de carcinome papillaire de la thyroïde ». Paris 11, 2008. http://www.theses.fr/2008PA114832.
Texte intégralAt first, the aim of this work was to identify an efficient sequence of siRNA against the ret/PTC1 oncogene involved in the development of papillary thyroid carcinoma. This sequence was shown to down-regulate the expression of ret/PTC1 oncogene in vitro and in vivo in mice after administration as a siRNA and after integration in a shRNA. As a second goal of this work, the active siRNA was formulated in nanoparticulate formulations to allow in vivo administration in mice bearing model ret/PTC1 tumor by intratumoral and intravenous routes. Some formulations of the vectorized siRNA were found efficient to reduce tumor growth including after intravenous administration. In the last part of this work, a methodology was developed to add cell recognition properties to the nanoparticles to further improve their targeting specificity toward the tumor cells
Gilbert, Marie. « Etude des mécanismes moléculaires impliqués dans la régulation de TTF-1 et recherche de nouvelles cibles thérapeutiques dans le carcinome papillaire de la thyroïde : rôle de l'oncogène RET/PTC1 et de la voie Wnt/Bêta-caténine ». Paris 11, 2010. http://www.theses.fr/2010PA114827.
Texte intégralThe papillary thyroid carcinoma (PTC) represents 80% of thyroid tumors and is characterized by a RET/PTC1 fusion oncogene (60-70% of cases) and the expression of the TTF-1 transcription factor. This factor leads to the expression of specific proteins of the thyroid as thyroglobulin and is found in many papillary cancers. The Wnt /β-catenin pathway is particularly studied because of its multiple roles in particular during development. It has also been extensively studied in many cancers and plays a fundamental role. These pathways were the subject of the work and the aim of the thesis was to show their roles and justify a targeted therapeutic approach. Our studies show that TTF-1 gene is regulated by the Wnt /β-catenin pathway in the PTC. In addition, we designed a specific and effective siRNA against the RET/PTC1 junction. The siRNA was vectorized with nanoparticles of squalene for a therapeutic use. We also showed that the siRNA induce TTF-1 expression and could be considered in the case of its therapeutic use in aggressive or resistant PTC
Buffet, Camille. « Anomalies moléculaires de la voie MAPK et cancer papillaire de la thyroïde : étude de deux phosphatases spécifiques de ERK, DUSP5 et DUSP6 ». Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T049/document.
Texte intégralPapillary thyroid cancer (PTC) is the most common endocrine malignancy. Mutually exclusive and activating alterations of the MAPK pathway (Mitogen-Activated Protein Kinases) are identified in 70% of cases. Common mutations found in PTCs are point mutation of the B-RAF (50%) and RAS genes (10%) as well as RET/PTC chromosomal rearrangements (10%). The hot spot B-RAFV600E mutation is the most frequently alteration identified and is connected with agressive clinical characteristics (high stage at diagnosis, high recurrence risk and death). These molecular events lead to constitutive activation of the MAPK pathway, resulting in MEK (Mitogen-activated Extracellular signal-Regulated Kinase) and ERK (Extracellular signal-Regulated Kinase) phosphorylation. ERK is negatively regulated by phosphatases and among them, Dual Specificity Phosphatases (DUSPs), ubiquitary expressed, in particular two ERK-specific phosphatases DUSP5 (nuclear) and DUSP6 (cytosolic). We hypothesized that these phosphatases could have tumor supressor properties (i.e. their loss would be associated with an increase in MAPK pathway activation) or may serve as a surrogate marker of MAPK pathway activation in the context of a negative feedback loop. We analysed regulation and expression of both phosphatases in 3 models: three PCCL3 cell lines (rat thyroid cells) expressing one of the most common oncogene identified in PTCs (RET/PTC3 or H-RASV12 or B-RAFV600E) under the control of a doxycycline-inducible promoter, human PTC-derived cell lines and human PTC. We demonstrated that MAPK pathway activation was correlated with induction of DUSP5 and DUSP6. These phosphatases are involved in a negative feedback loop that contributes to a tight regulation of phospho-ERK levels. DUSP5 and DUSP6 mRNA are overexpressed in human PTCs, especially in B-RAF mutated tumors suggesting a higher MAPK signaling output in these agressive PTCs. Silencing of DUSP5 and/or DUSP6 by small interfering RNA does not affect proliferation of human B-RAFV600E thyroid carcinoma-derived cell lines, suggesting the lack of tumor suppressor gene role. Compensatory changes in expression of DUSPs when a specific one is inactivated may explain this lack of effect. On the opposite, a DUSP6 pharmacological inhibitor induced a concentration dependent decrease in proliferation of human B-RAFV600E cells, suggesting « off-target » effect of this inhibitor. In a second part, we analysed the regulation of DUSP5 expression, which is a target of the MAPK pathway activation. We demonstrated, using pharmacological inhibitors, that DUSP5 is an early response gene, regulated mostly by the MAPK pathway, at the transcriptional level. Two contiguous CArG boxes that bind serum response factor (SRF) were found in a 1Kb promoter region, as well as several E twenty-six transcription factor family binding sites (EBS). These sites potentially bind Elk-1, a transcription factor activated by ERK1/2. Using wild type or mutated DUSP5 promoter reporters, we demonstrated that SRF plays a crucial role in serum induction of DUSP5 promoter activity, the proximal CArG box being important for SRF binding in vitro and in living cells. Moreover Elk-1 was bound in vitro to a promoter region containing the proximal CArG box and a putative EBS. Its specific binding to SRF was necessary to elicit promoter response to dominant positive Elk-VP16 and to enhance the response to serum stimulation. Altogether our results suggest that the MAPK pathway is more active in B-RAFV600E PTC than in PTC with other genetic alteration and could explain their clinical agressivity. DUSP5 and DUSP6, as well as phosphorylated MEK, are markers of activation of the MAPK pathway. Neither phosphatase has tumor suppressor properties in our thyroid cancer cell models. Our results suggest redundancy and functional compensation among DUSPs. (...)
Cailloux, Jérémy. « Rôle du système générateur d’espèces réactives de l’oxygène NOX4-p22phox dans la thyroïde humaine : implication dans la prolifération et la différenciation thyroïdienne ». Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T064/document.
Texte intégralBRAFV600E induced-TGF-β secretion down-regulates sodium iodide symporter (NIS) expression via NOX4-dependent ROS generation in papillary thyroid carcinoma. Abstract : Papillary thyroid cancer (PTC) is the most common thyroid pathology and BRAF point mutations account for 40-60% of tumors. BRAFT1799A is the most frequent BRAF mutation and BRAFV600E positive tumors are often associated with a significant loss of sodium/iodide symporter (NIS) expression. Clinical results on patients harboring thyroid cancer with BRAF mutation have recently shown that MAPK pathway inhibition does not fully reverts the BRAF-induced NIS repression. BRAFV600E expression induces secretion of functional TGF-β which is a repressor of thyroid specific genes such as NIS. Importantly, NOX4 has been shown to be prominently expressed in an increasing number of tumors, in particular in PTCs. In breast cancer cells, a critical mechanism for cancer development involves the transcriptional regulation of NOX4 by TGF-β. This result prompted us to test NOX4 as a ROS-producing candidate induced by BRAF-induced TGF-β. In this report, we first show in PTCs a correlation between BRAFV600E status, NOX4 overexpression, and low NIS expression level. Then, using BCPAP cells as an in vitro PTC model, we demonstrate that BRAFV600E controls NOX4 and p22phox expression via TGF-β signalling. The TGF-β autocrine loop activated by BRAFV600E induces NOX4 and p22phox expression at the transcriptional level via phosphorylated SMAD3. Both constitutively expressed proteins form a functional NADPH oxidase which produces high intracellular ROS levels. ROS scavengers increase the NIS expression at both mRNA and protein levels, and rescue a functional NIS, indicating that ROS are involved in the repression of NIS. Knocking down NOX4 with specific siRNAs reinduces NIS expression at both mRNA and protein levels. Altogether, these results show for the first time that NOX4-dependent ROS generation has a critical role in BRAF-induced NIS repression via the TGF-β/SMAD3 oncogenic signalling
Radom, Mickaëlle. « Rôle de la NADPH oxydase 4 (NOX4) dans la dédifférenciation des cellules tumorales thyroïdiennes porteuses de la mutation BRAFV600E ». Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASL012.
Texte intégralThe radioiodine therapy (RAI) constitutes the main treatment for differentiated thyroid cancer (DTC). This metabolic radiotherapy is based on the expression at thyroid cell basal membrane of the iodine transporter (NIS) encoded by SLC5A5 gene. BRAFV600E oncogene driver mutation is present in 40 to 60% of DTC. Locally advanced and metastatic papillary thyroid cancer (PTC) harboring BRAFV600E mutation have poor prognosis. BRAFV600E oncogene is a strong activator of MAPK signaling leading to a dedifferentiation process, which is associated with SLC5A5 gene repression and radioiodine therapy refractoriness. The RAI uptake constitutes a major challenge for treatment of patients and in this sense a new therapeutic approach consists of thyroid cell redifferentiation strategy. Our previous studies showed that BRAFV600E controls the NADPH oxidase (NOX4) expression and NOX4- derived ROS repress SLC5A5 gene. NOX4 inhibition reinduces NIS expression and the reversibility suggests a contribution to an epigenetic mechanism. The objective of the thesis was to determine the molecular and mechanistic events induced by NOX4-derived ROS that contribute to the repression of genes involved in differentiation process and in the efficiency of metabolic radiotherapy. Our results showed that NOX4 generates specific oxidative damage to DNA, which promotes the retention of epigenetic actors such as DNMTs through interaction with DNA repair proteins, thereby disrupting the DNA binding of thyroid differentiation transcription factors, PAX8 and NKX.2.1, and preventing gene transcription for prolonged periods. We also demonstrated an effect of BRAF/MEK inhibitors used clinically in NOX4- dependant epigenetic mechanism and a clinical interest of NOX4 inhibition in addition to BRAF/MEK inhibition in thyroid differentiation gene reinduction
Cazarin, de Menezes Juliana. « Role of NADPH Oxidase 4 in the Redox Regulation of the Sodium (Na+)/ iodide (I-) Symporter in Papillary Thyroid Cancer ». Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS068.
Texte intégralThe co-transporter Na+/ I- (NIS) mediates iodide uptake in thyroid gland which is a key step in hormonal biosynthesis. Iodide accumulation by thyrocytes is the basis of radioiodine therapy (RAI) which is the standard post-surgery therapeutic approach to efficiently eliminate remaining cancer lesions and metastasis of differentiated thyroid cancer (DTC). However, 5-10% of DTC patients become RAI-refractory which is indicative of poor prognosis. Reduced NIS expression and NIS internalization are in this process. BRAFV600E mutation is the most common genetic event in papillary thyroid cancers (PTCs), the most prevalent type of DTC. In rat thyrocytes, BRAFV600E induces secretion of TGFβ that activates Smad pathway resulting in NIS downregulation and overexpression of TGFβ is associated with NIS repression in patients. NADPH oxidase NOX4, a professional reactive oxygen species (ROS) generating enzyme, is a key mediator of TGFβ signaling in many cell types and has been previously demonstrated to be overexpressed thyroid cancers. To better understand the molecular mechanisms involved in PTC loss of iodine avidity, the aim of this work is to evaluate whether NOX4 is a key player of BRAFV600E-mediated NIS repression in thyroid cell lines. Using a normal rat thyroid cell line (PC-BRAF) we demonstrated that TGF-β administration or expression of BRAFV600E resulted in reduced NIS mRNA, reduced iodine uptake and increased NOX4 mRNA expression. NOX4 silencing or treatment with SIS3 an inhibitor of Smad pathway partially inhibited NIS repression indicating the implication of both Smad pathway and NOX4. To confirm this results we used a human thyroid cancer cell lines that harbors BRAFV600E mutation (BCPAP and 8505c) and observed an increase in NIS expression followed by BRAFV600E or NOX4 downregulation. Exogenous H2O2 induced DNA methyl-transferase 1 (DNMT1) enrichment in tight-chromatin protein fraction which was decreased by antioxidants or NOX4 silencing in BCPAP cells. TGF increased DNMT1 protein levels in chromatin-enriched cell fraction which was reversed by NADPH oxidase inhibitor, Diphenyleneiodonium (DPI). TGF-mediated DNA methylation and histone H3K9/K14 hypoacetylation were detected in NIS promoter, which is a repressive transcriptional mark. The data obtained suggest that NOX4 is a mediator of BRAFV600-TGF signaling and has a repressive role over NIS expression probably through epigenetic mechanisms. These results should lead to a better understanding of NIS expression regulation in thyroid cancer, bringing functional data for the development of new therapeutic tools
Lodyga, Monika. « Characterization of the Adaptor Protein XB130, a Tyrosine Kinase Substrate and a Novel Component of the Lamellipodia ». Thesis, 2011. http://hdl.handle.net/1807/31840.
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