Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

NKX2.5 is expressed in papillary thyroid carcinomas and regulates differentiation in thyroid cells

Authors: Ricardo Cortez Cardoso Penha, Luisa Aguirre Buexm, Fabiana Resende Rodrigues, Taciana Padilha de Castro, Maria Carolina S. Santos, Rodrigo Soares Fortunato, Denise P. Carvalho, Luciene C. Cardoso-Weide, Andrea C. F. Ferreira

Published in: BMC Cancer | Issue 1/2018

Login to get access

Abstract

Background

NKX2.5 is a transcription factor transiently expressed during thyroid organogenesis. Recently, several works have pointed out the oncogenic role of NKX2.5 in a variety of tumors. We therefore hypothesized that NKX2.5 could also play a role in thyroid cancer.

Methods

The validation of NKX2.5 expression was assessed by immunohistochemistry analysis in a Brazilian case series of 10 papillary thyroid carcinoma (PTC) patients. Then, the long-term prognostic value of NKX2.5 and its correlation with clinicopathologic features of 51 PTC patients was evaluated in a cohort with 10-years follow-up (1990–1999). Besides, the effect of NKX2.5 overexpression on thyroid differentiation markers and function was also investigated in a non-tumor thyroid cell line (PCCL3).

Results

NKX2.5 was shown to be expressed in most PTC samples (8/10, case series; 27/51, cohort). Patients who had tumors expressing NKX2.5 showed lower rates of persistence/recurrence (p = 0.013). Overexpression of NKX2.5 in PCCL3 cells led to: 1) downregulation of thyroid differentiation markers (thyrotropin receptor, thyroperoxidase and sodium-iodide symporter); 2) reduced iodide uptake; 3) increased extracellular H2O2 generation, dual oxidase 1 mRNA levels and activity of DuOx1 promoter.

Conclusions

In summary, NKX2.5 is expressed in most PTC samples analyzed and its presence correlates to better prognosis of PTC. In vitro, NKX2.5 overexpression reduces the expression of thyroid differentiation markers and increases ROS production. Thus, our data suggests that NKX2.5 could play a role in thyroid carcinogenesis.
Appendix
Available only for authorised users
Literature
1.
Tanaka M, Schinke M, Liao HS, Yamasaki N, Izumo S. NKX2.5 and Nkx2.6, homologs of Drosophila tinman, are required for development of the pharynx. Mol Cell Biol. 2001;21:4391–8.CrossRefPubMedPubMedCentral
2.
Dentice M, Cordeddu V, Rosica A, Ferrara AM, Santarpia L, Salvatore D, et al. Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis. J Clin Endocrinol Metab. 2006;91:1428–33.CrossRefPubMed
3.
De Felice M, Di Lauro R. Thyroid development and its disorders: genetics and molecular mechanisms. Endocr Rev. 2004;25:722–46.CrossRefPubMed
4.
Milenkovic M, De Deken X, Jin L, De Felice M, Di Lauro R, Dumont JE, et al. Duox expression and related H2O2 measurement in mouse thyroid: onset in embryonic development and regulation by TSH in adult. J Endocrinol. 2007;192:615–26.CrossRefPubMed
5.
Lints TJ, Parsons LM, Hartley L, Lyons I, Harvey RP. Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development. 1993;119:419–31.PubMed
6.
Nagel S, Kaufmann M, Drexler HG, MacLeod RA. The cardiac Homeobox gene NKX2-5 is deregulated by juxtaposition withBCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2). Cancer Res. 1993;63:5329–34.
7.
8.
Shibata K, Kajiyama H, Yamamoto E, Terauchi M, Ino K, Nawa A, Kikkawa F. Establishment and characterization of an ovarian yolk sac tumor cell line reveals possible involvement of NKX2.5 in tumor development. Oncology. 2008;74:104–11.CrossRefPubMed
9.
de Castro TP, Waissmann W, Simões TC, de Mello RC, Carvalho DP. Predictors for papillary thyroid cancer persistence and recurrence: a retrospective analysis with a 10-year follow-up cohort study. Clin Endocrinol. 2016;85:466–74.CrossRef
10.
Souza EC, Padrón AS, Braga WM, Andrade BM, Vaisman M, Nasciutti LE, et al. MTOR downregulates iodide uptake in thyrocytes. J Endocrinol. 2010;206:113–20.CrossRefPubMed
11.
Kasahara H, Usheva A, Ueyama T, Aoki H, Horikoshi N, Izumo S. Characterization of homo- and heterodimerization of cardiac Csx/NKX2.5 homeoprotein. J Biol Chem. 2001;276:4570–80.CrossRefPubMed
12.
Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3:1101–8.CrossRefPubMed
13.
Fortunato RS, Braga WM, Ortenzi VH, Rodrigues DC, Andrade BM, Miranda-Alves L, et al. Sexual dimorphism of thyroid reactive oxygen species production due to higher NADPH oxidase 4 expression in female thyroid glands. Thyroid. 2013;23:111–9.CrossRefPubMed
14.
Pachucki J, Wang D, Christophe D, Miot F. Structural and functional characterization of the two human ThOX/Duox genes and their 5′-flanking regions. Mol Cell Endocrinol. 2004;214:53–62.CrossRefPubMed
15.
Fusco A, Berlingieri MT, Di Fiore PP, Portella G, Grieco M, Vecchio G. One- and two-step transformations of rat thyroid epithelial cells by retroviral oncogenes. Mol Cell Biol. 1987;7:3365–70.CrossRefPubMedPubMedCentral
16.
Postiglione MP, Parlato R, Rodriguez-Mallon A, Rosica A, Mithbaokar P, Maresca M, Marians RC, Davies TF, Zannini MS, De Felice M, Di Lauro R. Role of the thyroid-stimulating hormone receptor signaling in development and differentiation of the thyroid gland. Proc Natl Acad Sci U S A. 2002;99:15462–7.CrossRefPubMedPubMedCentral
17.
Grasberger H, Refetoff S. Identification of the maturation factor for dual oxidase. Evolution of an eukaryotic operon equivalent J Biol Chem. 2006;281:18269–72.PubMed
18.
Rigutto S, Hoste C, Dumont JE, Corvilain B, Miot F, De Deken X. Duox1 is the main source of hydrogen peroxide in the rat thyroid cell line PCCl3. Exp Cell Res. 2007;313:3892–901.CrossRefPubMed
19.
Lim J, Thiery JP. Epithelial-mesenchymal transitions: insights from development. Development. 2012;139:3471–86.CrossRefPubMed
20.
Dohán O, De la Vieja A, Paroder V, Riedel C, Artani M, Reed M, Ginter CS, Carrasco N. The sodium/iodide symporter (NIS): characterization, regulation, and medical significance. Endocr Rev. 2003;24:48–77.CrossRefPubMed
21.
Carvalho DP, Ferreira AC. The importance of sodium/iodide symporter (NIS) for thyroid cancer management. Arq Bras Endocrinol Metabol. 2007;51:672–82.CrossRefPubMed
22.
Ameziane-El-Hassani R, Boufraqech M, Lagente-Chevallier O, Weyemi U, Talbot M, Métivier D, Courtin F, Bidart JM, El Mzibri M, Schlumberger M, Dupuy C. Role of H2O2 in RET/PTC1 chromosomal rearrangement produced by ionizing radiation in human thyroid cells. Cancer Res. 2010;70:4123–32.CrossRefPubMed
23.
Ameziane-El-Hassani R, Talbot M, de Souza Dos Santos MC, Al Ghuzlan A, Hartl D, Bidart JM, et al. NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation. Proc Natl Acad Sci U S A. 2015;112:5051–6.CrossRefPubMedPubMedCentral
24.
Dingal PC, Bradshaw AM, Cho S, Raab M, Buxboim A, Swift J, Discher DE. Fractal heterogeneity in minimal matrix models of scars modulates stiff-niche stem-cell responses via nuclear exit of a mechanorepressor. Nat Mater. 2015;14:951–60.CrossRefPubMed
25.
Wang J, Zhang H, Iyer D, Feng XH, Schwartz RJ. Regulation of cardiac specific nkx2.5 gene activity by small ubiquitin-like modifier. J Biol Chem. 2008;283:23235–43.CrossRefPubMedPubMedCentral
26.
Tuccilli C, Baldini E, Sorrenti S, Di Gioia C, Bosco D, Ascoli V, et al. Papillary thyroid cancer is characterized by altered expression of genes involved in the sumoylation process. J Biol Regul Homeost Agents. 2015;29:655–62.PubMed
27.
28.
Ellis RJ, Wang Y, Stevenson HS, Boufraqech M, Patel D, Nilubol N, et al. Genome-wide methylation patterns in papillary thyroid cancer are distinct based on histological subtype and tumor genotype. J Clin Endocrinol Metab. 2014;99:E329–37.CrossRefPubMed
29.
Sheng W, Qian Y, Wang H, Ma X, Zhang P, Diao L, et al. DNA methylation status of NKX2-5, GATA4 and HAND1 in patients with tetralogy of fallot. BMC Med Genet. 2013;6:46.
30.
Bhargav PR, Mishra A, Agarwal G, Agarwal A, Pradhan PK, Gambhir S, Verma AK, Mishra SK. Long-term outcome of differentiated thyroid carcinoma: experience in a developing country. World J Surg. 2010;34:40–7.CrossRefPubMed
31.
Nagel S, Venturini L, Przybylski GK, Grabarczyk P, Schmidt CA, Meyer C, Drexler HG, Macleod RA, Scherr M. Activation of miR-17-92 by NK-like homeodomain proteins suppresses apoptosis via reduction of E2F1 in T-cell acute lymphoblastic leukemia. Leuk Lymphoma. 2009;50:101–8.CrossRefPubMed
32.
Melo M, Gaspar da Rocha A, Batista R, Vinagre J, Martins MJ, Costa G, Ribeiro C, Carrilho F, Leite V, Lobo C, Cameselle-Teijeiro JM, Cavadas B, Pereira L, Sobrinho-Simões M, Soares P. TERT, BRAF, and NRAS in primary thyroid Cancer and metastatic disease. J Clin Endocrinol Metab. 2017;102(6):1898–907.CrossRefPubMed
Metadata
Title
NKX2.5 is expressed in papillary thyroid carcinomas and regulates differentiation in thyroid cells
Authors
Ricardo Cortez Cardoso Penha
Luisa Aguirre Buexm
Fabiana Resende Rodrigues
Taciana Padilha de Castro
Maria Carolina S. Santos
Rodrigo Soares Fortunato
Denise P. Carvalho
Luciene C. Cardoso-Weide
Andrea C. F. Ferreira
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4399-1

Other articles of this Issue 1/2018

BMC Cancer 1/2018 Go to the issue

Research article

The plasma glutamate concentration as a complementary tool to differentiate benign PET-positive lung lesions from lung cancer

Research article

High expression of the p53 isoform γ is associated with reduced progression-free survival in uterine serous carcinoma

Research article

Longitudinal autoantibody responses against tumor-associated antigens decrease in breast cancer patients according to treatment modality

Research article

The identification of H3F3A mutation in giant cell tumour of the clivus and the histological diagnostic algorithm of other clival lesions permit the differential diagnosis in this location

Research article

Immune landscape and in vivo immunogenicity of NY-ESO-1 tumor antigen in advanced neuroblastoma patients

Research article

The effects of shared decision-making compared to usual care for prostate cancer screening decisions: a systematic review and meta-analysis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits