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  • Review Article
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NADPH oxidases: new actors in thyroid cancer?

Nature Reviews Endocrinology volume 12, pages 485–494 (2016)Cite this article

Subjects

Key Points

  • Hydrogen peroxide (H2O2) is involved in both the physiology and pathology of the human thyroid gland, with roles both in hormone synthesis and in oxidative DNA damage

  • The NADPH oxidase/dual oxidase (NOX/DUOX) family are the major nonmitochondrial sources of reactive oxygen species in cells; the human thyroid gland expresses DUOX1, DUOX2 and NOX4

  • DUOX2 is the main source of H2O2 for hormone synthesis by thyroid peroxidase; the physiological functions of DUOX1 and NOX4 in human thyroid tissue are still unknown

  • Both DUOXs and NOX4 are overexpressed in human thyroid tumours, which suggests that these H2O2-generating enzymes might be involved in thyroid cancer pathogenesis

  • DUOX1 is upregulated in radiation-induced thyroid cancer, and DUOX1-dependent production of H2O2 promotes persistent DNA damage after human thyroid cells are exposed to ionizing radiation

  • Generation of H2O2 by NOX4 mediates oncogene-induced DNA damage and senescence in human thyroid cells

Abstract

Hydrogen peroxide (H2O2) is a crucial substrate for thyroid peroxidase, a key enzyme involved in thyroid hormone synthesis. However, as a potent oxidant, H2O2 might also be responsible for the high level of oxidative DNA damage observed in thyroid tissues, such as DNA base lesions and strand breakages, which promote chromosomal instability and contribute to the development of tumours. Although the role of H2O2 in thyroid hormone synthesis is well established, its precise mechanisms of action in pathological processes are still under investigation. The NADPH oxidase/dual oxidase family are the only oxidoreductases whose primary function is to produce reactive oxygen species. As such, the function and expression of these enzymes are tightly regulated. Thyrocytes express dual oxidase 2, which produces most of the H2O2 for thyroid hormone synthesis. Thyrocytes also express dual oxidase 1 and NADPH oxidase 4, but the roles of these enzymes are still unknown. Here, we review the structure, expression, localization and function of these enzymes. We focus on their potential role in thyroid cancer, which is characterized by increased expression of these enzymes.

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Figure 1: The NADPH oxidase family and the role of NOX2 in phagocytic innate immunity defence5,6,7,8.
Figure 2: Localization of DUOX proteins in human thyroid follicle and thyroid hormone synthesis119.
Figure 3: Cross-interaction between DUOX proteins and their partners.
Figure 4: Hypothetical model of the role of H2O2-generating NADPH oxidases in DNA damage in the thyroid.

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Acknowledgements

The authors would like to acknowledge the support of grants from Electricité de France (C.D./RB2015-09), Association pour la Recherche sur le Cancer (C.D./397161), Institut National du Cancer (C.D./2013-1-PLBIO-14-CNRS), Ligue Contre le Cancer (C.D./RS14/75-51), and Programmes Internationaux de Coopération Scientifique: CNRS-France/CNRST-Maroc (C.D. and R.A.-E-H/Afrique-Moyen Orient 2013).

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  1. Institut Gustave Roussy, UMR 8200 CNRS, 114 Rue Edouard Vaillant, Villejuif, F-94805, France

    Rabii Ameziane-El-Hassani, Martin Schlumberger & Corinne Dupuy

  2. Unité de Biologie et de Recherche Médicale, Centre National de l'Energie, des Sciences et des Techniques Nucléaires, BP 1382, Rabat, M-10001, Morocco

    Rabii Ameziane-El-Hassani

  3. University Paris-Saclay, Orsay, F-91400, France

    Martin Schlumberger & Corinne Dupuy

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  1. Rabii Ameziane-El-Hassani
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R.A.-E.-H. and C.D. researched data for the article and wrote the manuscript. All authors contributed to discussion of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Corinne Dupuy.

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Ameziane-El-Hassani, R., Schlumberger, M. & Dupuy, C. NADPH oxidases: new actors in thyroid cancer?. Nat Rev Endocrinol 12, 485–494 (2016). https://doi.org/10.1038/nrendo.2016.64

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