Thyroid Cancer and Circadian Clock Disruption

Abstract

Thyroid cancer (TC) represents the most common malignancy of the endocrine system, with an increased incidence across continents attributable to both improvement of diagnostic procedures and environmental factors. Among the modifiable risk factors, insulin resistance might influence the development of TC. A relationship between circadian clock machinery disfunction and TC has recently been proposed. The circadian clock machinery comprises a set of rhythmically expressed genes responsible for circadian rhythms. Perturbation of this system contributes to the development of pathological states such as cancer. Several clock genes have been found deregulated upon thyroid nodule malignant transformation. The molecular mechanisms linking circadian clock disruption and TC are still unknown but could include insulin resistance. Circadian misalignment occurring during shift work, jet lag, high fat food intake, is associated with increased insulin resistance. This metabolic alteration, in turn, is associated with a well-known risk factor for TC i.e., hyperthyrotropinemia, which could also be induced by sleep disturbances. In this review, we describe the mechanisms controlling the circadian clock function and its involvement in the cell cycle, stemness and cancer. Moreover, we discuss the evidence supporting the link between circadian clockwork disruption and TC development/progression, highlighting its potential implications for TC prevention, diagnosis and therapy.

Keywords: circadian misalignment; clock genes; insulin resistance; machinery; occupational and environmental factors; sleep disturbances; thyroid cancer.

Figure 1

Effect of circadian rhythm disruption on body health. Circadian alignment is associated with wellness and body health. Circadian clock malfunctioning induced by genetic factors (clock gene mutations) and/or environmental factors (inappropriate light exposure, sleep restriction, jetlag, shift work, irregular food intake) can lead to the development of several disorders including cancer, diabetes, cardiovascular disorders, endocrine diseases, inflammation, mental disorders, immune system alterations and reproductive disorders.

Figure 2

Molecular alterations in circadian clock gene machinery during thyroid nodule malignant transformation and progression. The circadian transcriptional/translation machinery physiologically acts through a core loop in which CLOCK/BMAL1 activate transcription by binding E-boxes in the promoters of target genes (PERs, CRYs, REV-ERBs, RORs, DECs, WEE1, c-MYC and other clock-controlled genes (CCGs)). In the same loop, the negative PERs and CRYs proteins multimerize and inhibit CLOCK/BMAL1 activity. Clock machinery is also regulated by an accessory loop, consisting of antagonizing transcription factors such as REV-ERBs (α−β) and RORs (α−β−γ), which regulate CLOCK/BMAL1 gene expression and CLOCK/BMAL1-mediated CCGs transcription through ROR-elements (RORE). During thyroid tumorigenesis, circadian misalignment is associated with an altered expression of several clock genes and other CCGs controlling cellular and metabolic functions. These molecular alterations may contribute to thyroid nodule malignant transformation and progression.