Deiodinases and Cancer

Nappi, Antonio; Stefano, Maria Angela De; Dentice, Monica; Salvatore, Domenico

doi:10.1210/endocr/bqab016

Cited by 21 publications

(12 citation statements)

References 83 publications

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“…Although D2 has been associated with different hallmarks of cancer as enhanced EMT, migration and invasion of cancer cells, and angiogenesis promotion 10 – 12 , 41 , the direct regulation by p53 raises the question of whether D2 can be involved in the DNA damage repair and in the genome stability.…”

Section: Discussionmentioning

confidence: 99%

Loss of p53 activates thyroid hormone via type 2 deiodinase and enhances DNA damage

et al. 2023

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The Thyroid Hormone (TH) activating enzyme, type 2 Deiodinase (D2), is functionally required to elevate the TH concentration during cancer progression to advanced stages. However, the mechanisms regulating D2 expression in cancer still remain poorly understood. Here, we show that the cell stress sensor and tumor suppressor p53 silences D2 expression, thereby lowering the intracellular THs availability. Conversely, even partial loss of p53 elevates D2/TH resulting in stimulation and increased fitness of tumor cells by boosting a significant transcriptional program leading to modulation of genes involved in DNA damage and repair and redox signaling. In vivo genetic deletion of D2 significantly reduces cancer progression and suggests that targeting THs may represent a general tool reducing invasiveness in p53-mutated neoplasms.

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Section: Discussionmentioning

confidence: 99%

Loss of p53 activates thyroid hormone via type 2 deiodinase and enhances DNA damage

et al. 2023

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“…The specific DNA binding sequences of TRs, called TR Response Elements (TREs), consist of the AGGTCA sequence as a half site, which is repeated in a direct, everted, or inverted manner in different promoters [14,15]. T4 is the main circulating hormone and is de-iodinized to T3 in target tissues by iodothyronine deiodinases DIO1 and DIO2 [16]. Another deiodinase, DIO3, further deiodinizes T3 and T4, producing the inactive forms T2 and reverse T3 (rT3), respectively.…”

Section: The Hypothalamic-pituitary-thyroid Axis and Systemic Effects...mentioning

confidence: 99%

The TSH/Thyroid Hormones Axis and Breast Cancer

Voutsadakis

2022

JCM

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Breast cancer, the most prevalent female carcinoma, is characterized by the expression of steroid nuclear receptors in a subset of cases. The most important nuclear receptor with prognostic and therapeutic implications is the Estrogen Receptor (ER), which is expressed in about three out of four breast cancers. The Progesterone Receptor (PR) and the Androgen Receptor (AR) are also commonly expressed. Moreover, non-steroid nuclear receptors, including the vitamin D receptor (VDR) and the thyroid receptors (TRs), are also present in breast cancers and have pathophysiologic implications. Circulating thyroid hormones may influence breast cancer risk and breast cancer cell survival, through ligating their canonical receptors TRα and TRβ but also through additional membrane receptors that are expressed in breast cancer. The expression of TR subtypes and their respective isotypes have diverse effects in breast cancers through co-operation with ER and influence on other cancer-associated pathways. Other components of the TSH/thyroid hormone axis, such as TSH and selenoiodinase enzymes, have putative effects in breast cancer pathophysiology. This paper reviews the pathophysiologic and prognostic implications of the thyroid axis in breast cancer and provides a brief therapeutic perspective.

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“…In addition, it is surmised that deiodinases, which activate thyroid hormones by converting T4 into T3 (type I and II) or inactivate them by degrading (type III), might play an important role in relation to malignant diseases. This tight intracellular control of thyroid hormone availability might be dysregulated in patients with cancer and might promote tumor development and progression [32,33]. A recent study by Lin Hung-Yung et al showed that reverse T3 (rT3), which results from the conversion of T4 to T3, may be a host factor supporting cancer growth [34].…”

Section: Thyroid Hormone Statusmentioning

confidence: 99%

Thyroid Hormone Replacement Therapy Is Associated with Longer Overall Survival in Patients with Resectable Gastroesophageal Cancer: A Retrospective Single-Center Analysis

Puhr

Reiter

El-Mahrouk

et al. 2021

Cancers

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Introduction: As thyroid hormones modulate proliferative pathways it is surmised that they can be associated with cancer development. Since the potential association of gastroesophageal cancer and thyroid disorders has not been addressed so far, the aim of this study was to investigate the association of thyroid hormone parameters with the outcome of these patients, so novel prognostic and even potentially therapeutic markers can be defined. Material and Methods: Clinical and endocrinological parameters of patients with resectable gastroesophageal cancer treated between 1990 and 2018 at the Vienna General Hospital, Austria, including history of endocrinological disorders and laboratory analyses of thyroid hormones at first cancer diagnosis were investigated and correlated with the overall survival (OS). Results: In a total of 865 patients, a tendency towards prolonged OS in hypothyroid patients (euthyroid, n = 647: median OS 29.7 months; hyperthyroid, n = 50: 23.1 months; hypothyroid, n = 70: 47.9 months; p = 0.069) as well as a significant positive correlation of thyroid hormone replacement therapy with the OS was observed (without, n = 53: median OS 30.6 months; with, n = 67: 51.3 months; p = 0.017). Furthermore, triiodothyronine (T3) levels were also associated with the OS (median OS within the limit of normal: 23.4, above: 32.4, below: 9.6 months; p = 0.045). Conclusion: Thyroid disorders and their therapeutic interventions might be associated with the OS in patients with resectable gastroesophageal cancer. As data on the correlation of these parameters is scarce, this study proposes an important impulse for further analyses concerning the association of thyroid hormones with the outcome in patients with gastroesophageal tumors.

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Deiodinases and Cancer

Cited by 21 publications

References 83 publications

Loss of p53 activates thyroid hormone via type 2 deiodinase and enhances DNA damage

Loss of p53 activates thyroid hormone via type 2 deiodinase and enhances DNA damage

The TSH/Thyroid Hormones Axis and Breast Cancer

Thyroid Hormone Replacement Therapy Is Associated with Longer Overall Survival in Patients with Resectable Gastroesophageal Cancer: A Retrospective Single-Center Analysis

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