Browsing by Author "Riesco Eizaguirre, Garcilaso"
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Item BRAF V600E Confers Male Sex Disease-Specific Mortality Risk in Patients With Papillary Thyroid Cancer.(Journal of Clinical Oncology, 2020) Wang, Fei; Riesco Eizaguirre, Garcilaso; Xing, MingzhaoPurpose To test whether the prognostic risk of male sex in papillary thyroid cancer (PTC) is determined by BRAF V600E and can thus be stratified by BRAF status. Patients and Methods We retrospectively investigated the relationship between male sex and clinicopathologic outcomes in PTC, particularly mortality, with respect to BRAF status in 2,638 patients (male, n = 623; female, n = 2,015) from 11 centers in six countries, with median age of 46 years (interquartile range, 35-58 years) at diagnosis and median follow-up time of 58 months (interquartile range, 26-107 months). Results Distant metastasis rates in men and women were not different in wild-type BRAF PTC but were different in BRAF V600E PTC: 8.9% (24 of 270) and 3.7% (30 of 817; P = .001), respectively. In wildtype BRAF PTC, mortality rates were 1.4% (five of 349) versus 0.9% (11 of 1175) in men versus women (P = .384), with a hazard ratio (HR) of 1.59 (95% CI, 0.55 to 4.57), which remained insignificant at 0.70 (95% CI, 0.23 to 2.09) after clinicopathologic multivariable adjustment. In BRAF V600E PTC, mortality rates were 6.6% (18 of 272) versus 2.9% (24 of 822) in men versus women (P = .006), with an HR of 2.43 (95% CI, 1.30 to 4.53), which remained significant at 2.74 (95% CI, 1.38 to 5.43) after multivariable adjustment. In conventional-variant PTC, male sex similarly had no effect in wild-type BRAF patients; mortality rates in BRAF V600E patients were 7.2% (16 of 221) versus 2.9% (19 of 662) in men versus women (P = .004), with an HR of 2.86 (95% CI, 1.45 to 5.67), which remained significant at 3.51 (95% CI, 1.62 to 7.63) after multivariable adjustment. Conclusion Male sex is a robust independent risk factor for PTC-specific mortality in BRAF V600E patients but not in wild-type BRAF patients. The prognostic risk of male sex in PTC can thus be stratified by BRAF status in clinical application.Item Circulating MicroRNA Profiles as Potential Biomarkers for Differentiated Thyroid Cancer Recurrence.(The Journal of Clinical Endocrinology & Metabolism, 2022) Jankovic Miljus, Jelena; Guillén-Sacoto, María Augusta; Makiadi-Alvarado, Jennifer; Wert-Lamas, León; Ramirez-Moya, Julia; Robledo, Mercedes; Santisteban, Pilar; Riesco Eizaguirre, GarcilasoContext: Circulating microRNAs (miRNAs) are emerging biomarkers of thyroid cancer. Objective: This study sought to identify the profile of circulating miRNAs and its response to human recombinant TSH (rhTSH) in thyroid cancer patients with recurrent/persistent disease. Methods: We obtained serum samples from 30 patients with differentiated thyroid cancer, 14 with recurrent/persistent disease and 16 with complete remission. We used next-generation sequencing to define the miRnomes along with a comprehensive quantitative PCR (qPCR) validation using 2 different platforms. We made a transversal study by comparing serum miRNA profiles of patients with or without recurrent/persistent disease and a longitudinal study looking at differences before and after rhTSH stimulation. Selected miRNAs were then studied in human thyroid cancer cell lines TPC-1, FTC-133, and OCUT-2 in response to TSH stimulation. Results: We could not demonstrate any consistent differences in serum profiles of known miRNAs between patients with and without recurrent/ persistent disease or before and after rhTSH stimulation. However, our sequencing data revealed 2 putative novel miRNAs that rise with rhTSH stimulation in the serums of patients with recurrent/persistent disease. We further confirmed by qPCR the upregulation of these putative miRNAs both in serums and in TSH-stimulated cells. We also show miRNAs that are good candidates for housekeeping genes in the serum of patients independently of the levels of TSH. Conclusions: The present study does not provide evidence that known miRNAs can be used as circulating markers for recurrence of thyroid cancer. However, we suggest that novel miRNA molecules may be related to thyroid cancer pathogenesis.Item Hsa-miR-139-5p is a prognostic thyroid cancer marker involved in HNRNPF-mediated alternative splicing.(International Journal of Cancer, 2020) Montero-Conde, Cristina; Graña-Castro, Osvaldo; Martín-Serrano, Guillermo; Riesco Eizaguirre, Garcilaso; Robledo, MercedesIt is critical to identify biomarkers and functional networks associated with aggressive thyroid cancer to anticipate diseaseprogression and facilitate personalized patient management. We performed miRNome sequencing of 46 thyroid tumorsenriched with advanced disease patients with a median follow-up of 96 months. MiRNome profiles correlated with tumor-specific histopathological and molecular features, such as stromal cell infiltration and tumor driver mutation. Differentialexpression analysis revealed a consistent hsa-miR-139-5p downexpression in primary carcinomas from patients withrecurrent/metastatic disease compared to disease-free patients, sustained in paired local metastases and validated in publiclyItem Identification of an interactome network between lncRNAs and miRNAs in thyroid cancer reveals SPTY2D1-AS1 as a new tumor suppressor.(Scientific Reports, 2022) Ramírez‑Moya, Julia; Wert‑Lamas, León; ; Fletcher, Alice; Wert‑Carvajal, Carlos; McCabe, Christopher J.; Santisteban, Pilar; Riesco Eizaguirre, Garcilaso; Acuña‑Ruiz, AdriánThyroid cancer is the most common primary endocrine malignancy in adults and its incidence is rapidly increasing. Long non-coding RNAs (lncRNAs), generally defined as RNA molecules longer than 200 nucleotides with no protein-encoding capacity, are highly tissue-specific molecules that serve important roles in gene regulation through a variety of different mechanisms, including acting as competing endogenous RNAs (ceRNAs) that ‘sponge’ microRNAs (miRNAs). In the present study, using an integrated approach through RNA-sequencing of paired thyroid tumor and non-tumor samples, we have identified an interactome network between lncRNAs and miRNAs and examined the functional consequences in vitro and in vivo of one of such interactions. We have identified a likely operative post-transcriptional regulatory network in which the downregulated lncRNA, SPTY2D1-AS1, is predicted to target the most abundant and upregulated miRNAs in thyroid cancer, particularly miR-221, a well-known oncomiRNA in cancer. Indeed, SPTY2D1-AS1 functions as a potent tumor suppressor in vitro and in vivo, it is downregulated in the most advanced stages of human thyroid cancer, and it seems to block the processing of the primary form of miR-221. Overall, our results link SPTY2D1-AS1 to thyroid cancer progression and highlight the potential use of this lncRNA as a therapeutic target of thyroid cancer.Item Impaired microRNA processing by DICER1 downregulation endows thyroid cancer with increased aggressiveness.(Oncogene, 2019) Ramírez Moya, Julia; Wert Lamas, León; Riesco Eizaguirre, Garcilaso; Santisteban, PilarThe global downregulation of microRNAs (miRNAs) is emerging as a common hallmark of cancer. However, the mechanisms underlying this phenomenon are not well known. We identified that the oncogenic miR-146b-5p attenuates miRNA biosynthesis by targeting DICER1 and reducing its expression. DICER1 overexpression inhibited all the miR-146binduced aggressive phenotypes in thyroid cells. Systemic injection of an anti-miR-146b in mice with orthotopic thyroid tumors suppressed tumor growth and recovered DICER1 levels. Notably, DICER1 downregulation promoted proliferation, migration, invasion, and epithelial-mesenchymal transition through miRNA downregulation. Our analysis of The Cancer Genome Atlas revealed a general decrease in DICER1 expression in thyroid cancer that was associated with a worse clinical outcome. Administration of the small-molecule enoxacin to promote DICER1 complex activity reduced tumor aggressiveness both in vitro and in vivo. Overall, our data confirm DICER1 as a tumor suppressor and show that oncogenic miR-146b contributes to its downregulation. Moreover, our results highlight a potential therapeutic application of RNA-based therapies including miRNA inhibitors and restoration of the biogenesis machinery, which may provide treatments for thyroid and other cancers.Item Inhibiting ERK dimerization ameliorates BRAF‑driven anaplastic thyroid cancer.(Cellular and Molecular Life Sciences, 2022) Zaballos, Miguel A.; Acuña‑Ruiz, Adrián; Morante, Marta; Riesco Eizaguirre, Garcilaso; Crespo, Piero; Santisteban, PilarBackground RAS-to-ERK signaling is crucial for the onset and progression of advanced thyroid carcinoma, and blocking ERK dimerization provides a therapeutic beneft in several human carcinomas. Here we analyzed the efects of DEL-22379, a relatively specifc ERK dimerization inhibitor, on the activation of the RAS-to-ERK signaling cascade and on tumor-related processes in vitro and in vivo. Methods We used a panel of four human anaplastic thyroid carcinoma (ATC) cell lines harboring BRAF or RAS mutations to analyze ERK dynamics and tumor-specifc characteristics. We also assessed the impact of DEL-22379 on the transcriptional landscape of ATC cell lines using RNA-sequencing and evaluated its therapeutic efcacy in an orthotopic mouse model of ATC. Results DEL-22379 impaired upstream ERK activation in BRAF- but not RAS-mutant cells. Cell viability and metastasisrelated processes were attenuated by DEL-22379 treatment, but mostly in BRAF-mutant cells, whereas in vivo tumor growth and dissemination were strongly reduced for BRAF-mutant cells and mildly reduced for RAS-mutant cells. Transcriptomics analyses indicated that DEL-22379 modulated the transcriptional landscape of BRAF- and RAS-mutant cells in opposite directions. Conclusions Our fndings establish that BRAF- and RAS-mutant thyroid cells respond diferentially to DEL-22379, which cannot be explained by the previously described mechanism of action of the inhibitor. Nonetheless, DEL-22379 demonstrated signifcant anti-tumor efects against BRAF-mutant cells in vivo with an apparent lack of toxicity, making it an interesting candidate for the development of combinatorial treatments. Our data underscore the diferences elicited by the specifc driver mutation for thyroid cancer onset and progression, which should be considered for experimental and clinical approaches.Item Patient Age–Associated Mortality Risk Is Differentiated by BRAF V600E Status in Papillary Thyroid Cancer.(Journal of Clinical Oncology, 2017) Shen, Xiaopei; Riesco Eizaguirre, Garcilaso; Xing, MingzhaoPurpose For the past 65 years, patient age at diagnosis has been widely used as a major mortality risk factor in the risk stratification of papillary thyroid cancer (PTC), but whether this is generally applicable, particularly in patients with different BRAF genetic backgrounds, is unclear. The current study was designed to test whether patient age at diagnosis is a major mortality risk factor. Patients and Methods We conducted a comparative study of the relationship between patient age at diagnosis and PTC-specific mortality with respect to BRAF status in 2,638 patients (623 men and 2,015 women) with a median age of 46 years (interquartile range, 35 to 58 years) at diagnosis and a median follow-up time of 58 months (interquartile range, 26 to 107 months). Eleven medical centers from six countries participated in this study. Results There was a linear association between patient age and mortality in patients with BRAF V600E mutation, but not in patients with wild-type BRAF, in whom the mortality rate remained low and flat with increasing age. Kaplan-Meier survival curves rapidly declined with increasing age in patients with BRAF V600E mutation but did not decline in patients with wild-type BRAF, even beyond age 75 years. The association between mortality and age in patients with BRAF V600E was independent of clinicopathologic risk factors. Similar results were observed when only patients with the conventional variant of PTC were analyzed. Conclusion The long-observed age-associated mortality risk in PTC is dependent on BRAF status; age is a strong, continuous, and independent mortality risk factor in patients with BRAF V600E mutation but not in patients with wild-type BRAF. These results question the conventional general use of patient age as a high-risk factor in PTC and call for differentiation between patients with BRAF V600E and wild-type BRAF when applying age to risk stratification and management of PTC.Item RAS Subcellular Localization Inversely Regulates Thyroid Tumor Growth and Dissemination.(Cancers, 2020) García Ibáñez, Yaiza; Riesco Eizaguirre, Garcilaso; Santisteban, Pilar; Casar, Berta; Crespo, PieroRAS mutations are the second most common genetic alteration in thyroid tumors. However, the extent to which they are associated with the most aggressive phenotypes is still controversial. Regarding their malignancy, the majority of RAS mutant tumors are classified as undetermined, which complicates their clinical management and can lead to undesired under- or overtreatment. Using the chick embryo spontaneous metastasis model, we herein demonstrate that the aggressiveness of HRAS-transformed thyroid cells, as determined by the ability to extravasate and metastasize at distant organs, is orchestrated by HRAS subcellular localization. Remarkably, aggressiveness inversely correlates with tumor size. In this respect, we also show that RAS site-specific capacity to regulate tumor growth and dissemination is dependent on VEGF-B secretion. Furthermore, we have identified the acyl protein thioesterase APT-1 as a determinant of thyroid tumor growth versus dissemination. We show that alterations in APT-1 expression levels can dramatically a ect the behavior of thyroid tumors, based on its role as a regulator of HRAS sublocalization at distinct plasma membrane microdomains. In agreement, APT-1 emerges in thyroid cancer clinical samples as a prognostic factor. As such, APT-1 levels could serve as a biomarker that could help in the stratification of HRAS mutant thyroid tumors based on their aggressiveness.Item The complex regulation of NIS expression and activity in thyroid and extrathyroidal tissues(Endocrine-Related Cancer, 2021) Riesco Eizaguirre, Garcilaso; Santisteban, Pilar; De la Vieja, AntonioThe sodium/iodide symporter (NIS) is an intrinsic plasma membrane protein that mediates active iodide transport into the thyroid gland and into several extrathyroidal tissues. NIS-mediated iodide uptake plays a pivotal role in the biosynthesis of thyroid hormones, of which iodide is an essential constituent. For 80 years, radioiodide has been used for the diagnosis and treatment of thyroid cancer, a successful theranostic agent that is extending its use to extrathyroidal malignancies. The purpose of this review is to focus on the most recent findings regarding the mechanisms that regulate NIS both in thyroid and extra-thyroidal tissues. Among other issues, we discuss the different transcriptional regulatory elements that govern NIS transcription in different tissues, the epigenetic modifications that regulate its expression, and the role that miRNAs play in fine-tuning NIS after being transcribed. A review on how hormones, cytokines, and iodide itself regulate NIS is provided. We also review the present stage of understanding NIS dysregulation in cancer, occupied mainly by convergent signaling pathways and by new insights in the route that NIS follows through different subcellular compartments to the plasma membrane. Furthermore, we cover NIS distribution and function in the increasing number of extrathyroidal tissues that express the symporter, as well as the role that NIS plays in tumor progression independently of its transport activity.Item Validation of dynamic risk stratification and impact of BRAF in risk assessment of thyroid cancer, a nation-wide multicenter study.(Frontiers in Endocrinology, 2023) Pérez Fernández, Laura; Sastre, Julia; Zafón, Carles; Oleaga, Amelia; Castelblanco, Esmeralda; Capel, Ismael; Galofre, Juan C.; Guadalix-Iglesias, Sonsoles; De la Vieja, Antonio; Riesco Eizaguirre, GarcilasoIntroduction: The dynamic risk stratification (DRS) is a relatively new system in thyroid cancer that considers the response to primary treatment to improve the initial risk of recurrence. We wanted to validate DRS system in a nationwide multicenter study and explore if the incorporation of BRAFV600E into DRS helps to better categorize and predict outcomes. Materials and methods: Retrospective study of 685 patients from seven centers between 1991 and 2016, with a mean age of 48 years and a median follow-up time of 45 months (range 23-77). The overall BRAFV600E prevalence was 53.4%. We classified patients into four categories based on DRS (‘excellent’, ‘indeterminate’, ‘biochemical incomplete’, and ‘structural incomplete’ response). Cox regression was used to calculate adjusted hazard ratios (AHR) and proportions of variance explained (PVEs). Results: We found 21.6% recurrences and 2.3% cancer-related deaths. The proportion of patients that developed recurrence in excellent, indeterminate, biochemical incomplete and structural incomplete response to therapy was 1.8%, 54%, 91.7% and 96.2% respectively. Considering the outcome at the end of the follow up, patients showed no evidence of disease (NED) in 98.2, 52, 33.3 and 25.6% respectively. Patients in the structural incomplete category were the only who died (17.7%). Because they have similar outcomes in terms of NED and survival, we integrated the indeterminate and biochemical incomplete response into one unique category creating the 3-tiered DRS system. The PVEs of the AJCC/TNM staging, ATA risk classification, 4-tiered DRS, and 3-tiered DRS to predict recurrence at five years were 21%, 25%, 57% and 59% respectively. BRAFV600E was significantly associated with biochemical incomplete response (71.1 vs 28.9%) (HR 2.43; 95% CI, 1.21 to 5.23; p=0.016), but not with structural incomplete response or distant metastases. BRAF status slightly changes the AHR values of the DRS categories but is not useful for different risk grouping. Conclusions: This is the first multicenter study to validate the 4-tiered DRS system. Our results also show that the 3-tiered DRS system, by integrating indeterminate and biochemical incomplete response into one unique category, may simplify response to therapy keeping the system accurate. BRAF status does not provide any additional benefit to DRS.