Percorrer por autor "Rodrigues, Lia"
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- DGCR8 microprocessor subunit mutation and expression deregulation in thyroid lesionsPublication . Rodrigues, Lia; Canberk, Sule; Macedo, Sofia; Soares, Paula; Vinagre, JoãoDeregulation of microRNA (miRNA) processing is a driver event in several tumours including thyroid cancer. DiGeorge Critical Region 8 (DGCR8) gene holds a critical role in miRNA biogenesis, as a microprocessor complex component, and in the development of the thyroid. Previous studies identified a DGCR8 mutation – the variant c.1552G>A p.(E518K) – in cases of thyroid cancer and proposed to cause a familial syndrome characterized by multinodular goitre (MNG) and schwannomatosis. The goal of this study was to characterize the variant p.(E518K) of DGCR8 in thyroid lesions and evaluate its expression.
- DICER1 and DGCR8 in thyroid tumorigenesis: miRNA biogenesis and histopathologic diversityPublication . Rodrigues, Lia; Martins, Rui Sousa; Máximo, Valdemar; Soares, Paula; Vinagre, João; Nosé, Vânia; Canberk, Sule; Rodrigues, LiaThis review examines the emerging roles of DICER1 and DGCR8, key components of the miRNA biogenesis pathway, in thyroid pathogenesis, with a particular focus on their association with oncocytic morphology. Recent findings have expanded our understanding of DICER1 syndrome and DGCR8-related thyroid disorders, revealing a broader spectrum of thyroid lesions associated with mutations in these genes than previously recognised. We analyse the current literature on DICER1 and DGCR8 mutations in thyroid pathology, synthesising data from both basic science and pathological studies. The review explores recent findings on oncocytic features in some DICER1-mutated thyroid lesions, acknowledging that this association remains under investigation. The manuscript details the molecular mechanisms underlying DICER1 and DGCR8 mutations, including their impact on miRNA processing and subsequent effects on gene expression and cellular function. We discuss the diverse range of thyroid lesions associated with these mutations, from benign follicular nodular disease to aggressive carcinomas. The clinical implications of these findings are significant, as recognising DICER1 and DGCR8-related thyroid lesions can lead to improved patient management, including genetic counselling and surveillance for other associated malignancies. We propose an algorithm for identifying DICER1-related thyroid lesions, with a focus on oncocytic tumours, to aid clinicians and pathologists in recognising these entities. This emerging field promises to refine the diagnosis, management, and treatment of thyroid disorders associated with miRNA biogenesis pathway alterations, potentially leading to novel diagnostic and therapeutic approaches.
- Exploring the genetic links between voltage-gated potassium channels and familial non-medullary thyroid carcinoma: a family studyPublication . Teixeira, Elisabete; Rodrigues, Lia; Cardoso, Marta; Fernandes, Cláudia; Paula, Arnaud da Cruz; Lima, Raquel; Ferreira, Marta; Martins, Teresa; Fernandes, Andreia; Rodrigues, Fernando; Prazeres, Hugo; Soares, Paula; Rodrigues, LiaOur team identified a family where 5 elements developed thyroid cancer between the ages of 26 and 38. Since no syndromic form of the disease was found, the diagnosis was of familial non-medullary thyroid carcinoma (FNMTC). Our team employed Whole-Exome Sequencing (WES) and identified a new potentially pathogenic germline mutation in the KCNB2 gene [ p.(Gly106Arg)]. KCNB2 encodes a voltage-gated potassium channel (vgKCN), and the detected missense mutation is localized in the tetramerization domain of the protein, possibly affecting its assembly and KC efflux. Since KC efflux by the cell is a necessary condition for cellular homeostasis, channel disruption can impact the function of other ion channels nearby. Mice studies showed that KCNE2 disruption indirectly impairs sodium-iodide symporter (NIS) function, and therefore iodide uptake by the cell, resulting in hypothyroidism or follicular nodular disease. Hypothesis By indirect effect on NIS function vgKCN mutations may increase predisposition to thyroid cancer and interfere with radioiodine (RAI) therapy response. We conducted in silico studies using two different NGS databases, TCGA and one in-house oncocytic tumors database (513 and 18 patients, respectively). Alterations in 59 genes were searched for copy-number variation, point mutations and other genetic alterations. in vitro assays using the FRTL-5 cell line are being performed. FRTL-5 cells were transfected with overexpression vectors containing either KCNB2 wild-type or KCNB2 mutated sequences, and the empty vector (EV) as a negative control. Expression of thyroid markers (e.g. NIS, TSH receptor, Thyroglobulin and TPO) was evaluated by qPCR and cell viability by PrestoBlue assay. Protein expression of thyroid markers will be assessed by Western blot. Cell cycle and apoptosis through flow cytometry, cell morphology by phalloidin assay, and cell colony formation by crystal violet. Transformed cells will further be treated with Guangxitoxin-1E, a potent KCNB1 / KCNB2 inhibitor. Our in silico results show that vgKCN mutations are rare events in thyroid cancer [19/488 (4%) in TCGA; 3/18 (17%) in our in-house database]. BRAF and NRAS alterations are frequent events in vgKCN altered tumors (58% and 16%, respectively). No KCNB2 pathogenic mutations were observed. vgKCN mutations were not correlated with patient prognosis. Our in vitro preliminary results show that KCNB2 mutated cells present higher expression of the channel than KCNB2 wild-type cells. No differences in cell viability were found between KCNB2 wild-type and mutated cells. If confirmed, vgKCN mutations may identify patients with altered RAI response, serving as thyroid cancer markers and potential pharmacological targets.
- Generation of an obese diabetic mouse model upon conditional Atrx disruptionPublication . Gaspar, Tiago Bordeira; Jesus, Tito Teles; Azevedo, Maria Teresa; Macedo, Sofia; Soares, Mariana Alves; Martins, Rui Sousa; Leite, Rúben; Rodrigues, Lia; Rodrigues, Daniela Ferreira; Cardoso, Luís; Borges, Inês; Canberk, Sule; Gärtner, Fátima; Miranda-Alves, Leandro; Lopes, José Manuel; Soares, Paula; Vinagre, JoãoATRX mutations occur in up to 17% of human pancreatic neuroendocrine tumours (PanNETs), and recent evidence points towards its inability to drive PanNET formation in mouse pancreas while predisposing individuals to inflammageing. Aiming to explore the additional non-tumourigenic consequences of Atrx deletion, we characterised an aged series of Atrx conditional disruption in β cells using the Pdx1 promoter. Homozygous mice (P.AtrxHOM) exhibited obesity, diabetes, glucose intolerance, and pancreatic adiposity at a higher extent than age- and sex-matched controls (P.AtrxWT).
- Unraveling the significance of DGCR8 and miRNAs in thyroid carcinomaPublication . Rodrigues, Lia; Paula, Arnaud Da Cruz; Soares, Paula; Vinagre, JoãoMicroRNAs (miRNAs) act as negative regulators for protein-coding gene expression impacting cell proliferation, differentiation, and survival. These miRNAs are frequently dysregulated in cancer and constitute classes of blood-based biomarkers useful for cancer detection and prognosis definition. In thyroid cancer (TC), the miRNA biogenesis pathway plays a pivotal role in thyroid gland formation, ensuring proper follicle development and hormone production. Several alterations in the miRNA biogenesis genes are reported as a causality for miRNA dysregulation. Mutations in microprocessor component genes are linked to an increased risk of developing TC; in particular, a recurrent mutation affecting DGCR8, the E518K. In this review, we explore these novel findings and resume the current state-of-the-art in miRNAs in thyroid carcinomas.