The complex regulation of NIS expression and activity in thyroid and extrathyroidal tissues

The 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.post-print5810 K

Impaired microRNA processing by DICER1 downregulation endows thyroid cancer with increased aggressiveness.

The 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.post-print3221 K

Ras subcellular localization inversely regulates thyroid tumor growth and dissemination

RAS 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 sitespecific 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 affect 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.PC lab is supported by grant RTI2018-096658B-100 from the Spanish Ministry of Science (MICIU/AEI/FEDER, UE). Santisteban, Riesco and Crespo Laboratories are supported jointly by grants from Asociación Española Contra el Cancer (AECC; GCB141423113) and CIBERONC from the Instituto de Salud Carlos III (ISCIII). PS acknowledges support from: SAF2016-75531-R (MINECO/FEDER, UE); B2017/BMD-3724 Tironet2 (Comunidad de Madrid) and PID2019-105303RB-I00/AEI/10.13039/501100011033 from Ministerio de Ciencia e Innovación (MICIN). B.C is funded by Retos Jóvenes Investigadores grant SAF2015-73364-JIN (MICIU/AEI/FEDER, UE), a PIE grant from Consejo Superior de Investigaciones Científicas (CSIC)- MICIU and the Ramón y Cajal Research Program (MICIU, RYC2018-024004-I)

Hsa-miR-139-5p is a prognostic thyroid cancer marker involved in HNRNPF-mediated alternative splicing.

It 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 publiclypost-print1,62 M

BRAF V600E Status Sharply Differentiates Lymph Node Metastasis-associated Mortality Risk in Papillary Thyroid Cancer

[Context]: How lymph node metastasis (LNM)-associated mortality risk is affected by BRAF V600E in papillary thyroid cancer (PTC) remains undefined. [Objective]: To study whether BRAF V600E affected LNM-associated mortality in PTC. [Design, Setting, and Participants]: We retrospectively analyzed the effect of LNM on PTC-specific mortality with respect to BRAF status in 2638 patients (2015 females and 623 males) from 11 centers in 6 countries, with median age of 46 [interquartile range (IQR) 35-58] years and median follow-up time of 58 (IQR 26-107) months. [Results]: Overall, LNM showed a modest mortality risk in wild-type BRAF patients but a strong one in BRAF V600E patients. In conventional PTC (CPTC), LNM showed no increased mortality risk in wild-type BRAF patients but a robustly increased one in BRAF V600E patients; mortality rates were 2/659 (0.3%) vs 4/321 (1.2%) in non-LNM vs LNM patients (P = 0.094) with wild-type BRAF, corresponding to a hazard ratio (HR) (95% CI) of 4.37 (0.80-23.89), which remained insignificant at 3.32 (0.52-21.14) after multivariate adjustment. In BRAF V600E CPTC, morality rates were 7/515 (1.4%) vs 28/363 (7.7%) in non-LNM vs LNM patients (P < 0.001), corresponding to an HR of 4.90 (2.12-11.29) or, after multivariate adjustment, 5.76 (2.19-15.11). Adjusted mortality HR of coexisting LNM and BRAF V600E vs absence of both was 27.39 (5.15-145.80), with Kaplan-Meier analyses showing a similar synergism. [Conclusions]: LNM-associated mortality risk is sharply differentiated by the BRAF status in PTC; in CPTC, LNM showed no increased mortality risk with wild-type BRAF but a robust one with BRAF mutation. These results have strong clinical relevance.This work was supported partly by the following funding at the individual participating centers: Polish National Center of Research and Development MILESTONE Project—molecular diagnostics and imaging in individualized therapy for breast, thyroid and prostate cancer, grant No. STRATEGMED2/267398/4/ NCBR/2015 (Poland, AC, BJ); Grants No. PID2019-105303RB-I00 (AEI from MICINN), GCB14142311CRES (AECC Foundation), and B2017/BMD-3724 TIRONET2-CM (Spain; PS and GR-E); Grant No. AZV 16-32665A and MH CZ-DRO (Institute of Endocrinology-EU, 00023761) (Czech Republic; BB, VS); NIH/ National Institute on Aging Grant No. 5R03AG042334-02 (LY); and grants from the Qingdao Science and Technology Project for People’s Livelihood No.13-1-3-58-nsh (China; FW) and the Innovative Platform Project of Qingdao No.12-1-2-15-jch (China; YW)

Comments to SEOM clinical guidelines for the treatment of thyroid cancer

Letter to Editor On behalf of the Thyroid Cancer Committee from the Spanish Society of Endocrinology and Nutrition (SEEN).-- et al.Peer Reviewe

Bases moleculares de las metástasis refractarias al yodo radioactivo en el cáncer de tiroides: nueva aproximación a la terapia génica del cáncer con NIS

Tesis doctoral inédita realizada en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. y el Instituto de Investigaciones Biomédicas 'Alberto Sols'. Fecha de lectura: 22 de Abril de 2010

Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer

PMID:23571588.-- et al.[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 amedian 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 mutationnegative 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. ©2013 American Medical Association. All rights reserved.Funding/Support: This project was supported by National Institutes of Health (NIH) grants R01CA134225 and R01CA113507 to Dr Xing. The statistical effort of Ms Carson for this project was supported by grant UL1RR025005 from the National Center for Advancing Translational Sciences and the NIH Roadmap for Medical Research. In addition, the studies at individual centers were supported as follows: the Ministry of Science and Higher Education Research grants N N403 194340 and N N401 612440 to Drs Czarniecka and Jarzab, respectively(Poland); grant NIDCR/NCI SPORE P50DE019032 to Dr Sindransky (United States); grants BFU2010–16025, RD06/0020/0060-RD12/0036/0030 FIS, ISCIII, and S2011/BMD-2328TIRONET to Dr Santisteban (Spain); grant NIH-R01-CA50706 and Byrne Foundation funding to Dr Fagin (United States); grants from Fondazione Cassa di Risparmio di Perugia and Associazione Italiana per la Ricerca sul Cancro (IG 9338) (Italy) and the Beadle Family Foundation (San Antonio, Texas) to Dr Puxeddu; grant IGA MHCRNT13901–4 to Drs Sykorova and Bendlova (Czech Republic); and grants from the New South Wales Cancer Institute to Dr O’Neill and from the Cancer Council of New South Wales to Dr Clifton-Bligh (Australia).Peer Reviewe

A perspective view of sodium iodide symporter research and its clinical implications

The sodium iodide symporter (NIS) is an intrinsic plasma membrane protein that mediates active iodide transport into the thyroid gland and into several extrathyroidal tissues, in particular the lactating mammary gland. Cloning and molecular characterization of the NIS have allowed the investigation of its key role in thyroid physiology as well as its potential pathophysiological and therapeutic implications in benign and malignant thyroid diseases. Similarly, elucidating the mechanisms underlying the regulation of NIS in lactating mammary gland and breast cancer, in which more than 80% of cases express endogenous NIS, may lead to findings that have novel implications for pathophysiology and therapy. Two approaches may, in the future, pave the way to extend the use of radioiodide treatment to nonthyroidal cancer. One is based on the reinduction of endogenous NIS expression in thyroid and breast cancer by targeting the main mechanisms involving tumoral transformation and dedifferentiation. The other is based on the application of NIS as a novel cytoreductive gene therapy strategy. NIS offers the unique advantage that it can be used both as a reporter and as a therapeutic gene, so that it is possible to image, monitor, and treat the tumor with radioiodide, just as in differentiated thyroid cancer. This review summarizes the main recent findings in NIS research that have a direct impact on diagnosis and therapeutic management. © 2006 Society of the European Journal of Endocrinology.We are grateful to Ministerio de Educación y Ciencia (Grant BFU 2004-03 169) and Instituto de Salud Carlos III (Grants FIS: RCMN (C03/08), RCGC, C03/10, and PI 041216), Spain for supporting our work. G Riesco-Eizaguirre is recipient of a Grant for MD training from FIS, Instituto de Salud Carlos III (Spain).Peer Reviewe