THYROIDANTIOXIDANT

Role of the Keap1/Nrf2 antioxidant response system in thyroid gland homeostasis and thyroid cancer

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 Obiettivo del progetto (Objective)

'Recently, it has been discovered that the thyroid gland has increased ability to withstand oxidative stress compared to other organs. This important feature allows the gland to maintain its homeostasis in the face of increased burden of free radicals produced during iodine metabolism for thyroid hormone synthesis. Iodine deficiency and goiter are associated with increased oxidative stress in the thyroid. While some antioxidant enzymes are known to be upregulated in the thyroid under such conditions, the broader regulatory mechanisms of oxidative stress resistance remain unknown. The proposed research aims to investigate the role of the major antioxidant response system orchestrated by the transcription factor Nrf2 in thyroid gland homeostasis and thyroid cancer. Specifically, it will examine whether Nrf2 regulates the thyroid’s antioxidant defenses; whether Nrf2 activity in the thyroid is altered during iodine deficiency and goitrogenesis; and whether constitutive Nrf2 activation by somatic mutations is associated with thyroid cancer. These investigations will utilize mouse knockouts of Nrf2 and wild-type animals, primary thyroid cell cultures derived from these mice, and archived thyroid cancer samples from human subjects. This work has implications for the management of iodine deficiency and the prevention of thyroid carcinogenesis. This interdisciplinary research project will be executed by Dr. Gerasimos Sykiotis, a translational investigator who has prior research experience in thyroid gland pathophysiology and has acquired state-of-the-art expertise with the Nrf2 antioxidant response system in the country of origin (USA). The University of Patras Medical Center is a highly qualified host organization as it has in place both the nrf2-/- animals and the human thyroid cancer samples. Lasting professional integration, international collaborations with the USA and European countries, and advanced European competitiveness are features of this proposal.'

Introduzione (Teaser)

European researchers investigated the protective mechanism in the thyroid gland to resist oxidative stress. Project findings have important consequences for thyroid cancer.

Descrizione progetto (Article)

Oxidative stress causes protein and lipid damage as well as mutations and epigenetic perturbations, thereby leading to disorders like cancer and neurodegeneration. The thyroid gland has antioxidant and detoxification enzymes that helps it withstand oxidative stress and maintain homeostasis during iodine metabolism for hormone synthesis. Surprisingly, the underlying mechanisms are yet to be elucidated.

In oxidative stress, NFE2-related transcription factor 2 (Nrf2) accumulates in the nucleus and transcriptionally activates protective genes through antioxidant response elements (AREs) in their regulatory sequences. Also it is suppressed during normal aging and aberrantly activated in many cancers. The EU-funded http://www.thyroid.eu/ (THYROIDANTIOXIDANT) (Role of the Keap1/Nrf2 antioxidant response system in thyroid gland homeostasis and thyroid cancer) project investigated the role of Nrf2 in thyroid gland homeostasis and thyroid cancer.

Scientists manipulated the Nrf2 pathway experimentally to find that activation increases resistance to oxidative insults, whereas inhibition compromises thyroid cell survival. In addition, Nrf2 controlled the expression of genes fundamental for thyroid hormone synthesis and was essential for thyroid autoregulation in response to iodine availability.

With respect to thyroid cancer, genetic analysis of archived samples revealed no mutations in Nrf2. However, the pathway was indeed activated compared to normal thyroid tissue, indicating that other genetic or epigenetic events must be implicated. An activated Nrf2 pathway possibly translates into protection of transformed thyroid cells from oxidative stress.

Collectively, the project results underscore the role of Nrf2 in thyroid gland maintenance and in thyroid cancer. Nrf2 inhibitors are currently in development by several companies and might be useful in treating radioiodine-refractory or metastatic thyroid cancer.