Nitrotyrosine, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) are increased in thyroid tumors from children and adolescents
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Updated: Jul 9, 2026

An Orthotopic Mouse Model of Anaplastic Thyroid Carcinoma
Published on: April 17, 2013
1Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Abstract:
Nitric oxide (NO) is a reactive cell signal that controls vascular tone and is generated by inducible (iNOS), endothelial (eNOS) and neuronal (nNOS) NO synthase (NOS). We hypothesized that NO could be important for growth of thyroid tumors and tested this hypothesis, by staining 41 papillary thyroid carcinoma (PTC), 9 follicular thyroid carcinoma (FTC), and 15 benign thyroid lesions for iNOS, eNOS and nitrotyrosine (N-TYR). Staining intensity was determined by 2 blinded, independent examiners, and quantified from grade 1 (absent) to grade 4 (intense). Average N-TYR staining of benign adenomas (2.5+/-0.42, p=0.009), PTC (3.10+/-0.12, p=0.001), FTC (2.44+/-0.30, p=0.001), and autoimmune lesions (3.25+/-0.48, p=0.019) were greater than that of multinodular goiter (1.0 for all 3) and surrounding normal thyroid (1.1+/-0.1). Average iNOS staining of benign adenomas (2.6+/-0.37), PTC (2.7+/-0.16), FTC (2.4+/-0.26) and autoimmune lesions (3.5+/-0.29) were all greater than that of surrounding normal thyroid (1.1+/-0.1, p<0.008), but there were too few multinodular goiters to achieve a significant difference (no.=2, 3.0+/-1.0). Average eNOS staining of benign adenomas (2.9+/-0.40), multinodular goiters (3.5+/-0.5), PTC (3.24+/-0.18), FTC (3.5+/-0.50), and autoimmune lesions (2.8+/-0.6) were also greater than that of surrounding normal thyroid (mean=1.4+/-0.2, p<0.001). N-TYR staining correlated with that of vascular endothelial growth factor (VEGF, r=0.36, p=0.007) and the number of lymphocytes/high power field (r=0.39, p=0.004). Recurrent disease developed only from carcinoma with moderate-intense N-TYR staining, but there were too few recurrent tumors to achieve statistical significance (p=0.08). We conclude that NO is produced by benign adenomas, PTC and FTC suggesting that NO could be important in vascularization of thyroid tumors and autoimmune thyroid diseases.
Insights
Nitric oxide (NO) is elevated in thyroid tumors and autoimmune thyroid diseases. This suggests NO plays a role in thyroid tumor vascularization and disease progression.
Area of Science:
- Endocrinology
- Oncology
- Immunology
Background:
- Nitric oxide (NO) is a critical cell signaling molecule involved in vascular tone regulation.
- NO is synthesized by three main isoforms of nitric oxide synthase (NOS): inducible (iNOS), endothelial (eNOS), and neuronal (nNOS).
Purpose of the Study:
- To investigate the role of NO in the growth of thyroid tumors.
- To determine the expression levels of iNOS, eNOS, and nitrotyrosine (N-TYR) in various thyroid lesions.
Main Methods:
- Immunohistochemical staining for iNOS, eNOS, and N-TYR was performed on 41 papillary thyroid carcinomas (PTC), 9 follicular thyroid carcinomas (FTC), and 15 benign thyroid lesions.
- Staining intensity was quantified by two independent examiners on a scale of 1 (absent) to 4 (intense).
- Correlations between N-TYR staining and vascular endothelial growth factor (VEGF) and lymphocyte count were analyzed.
Main Results:
- Elevated N-TYR, iNOS, and eNOS staining were observed in benign adenomas, PTC, FTC, and autoimmune thyroid lesions compared to normal thyroid tissue.
- N-TYR staining showed a positive correlation with VEGF expression and lymphocyte infiltration.
- Preliminary data suggested a potential link between moderate-to-intense N-TYR staining and recurrent disease in carcinomas.
Conclusions:
- NO is produced in benign and malignant thyroid tumors, as well as in autoimmune thyroid diseases.
- These findings suggest that NO may be important for the vascularization of thyroid tumors and in the pathogenesis of autoimmune thyroid conditions.
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