Circadian Clock Characteristics Are Altered in Human Thyroid Malignant Nodules
T. Mannic, P. Meyer, F. Triponez, M. Pusztaszeri, G. Le Martelot, O. Mariani, D. Schmitter, D. Sage, J. Philippe, C. Dibner
The Journal of Clinical Endocrinology & Metabolism, in press.
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Context: Circadian clock represents the body's molecular time-keeping system. Recent findings revealed strong changes of clock gene expression in various types of human cancers.
Objective: Due to emerging evidence on the connection between circadian oscillator, cell cycle and oncogenic transformation, we aimed to characterize the circadian clockwork in human benign and malignant thyroid nodules.
Design: Clock transcript levels were assessed by quantitative RT-PCR in thyroid tissues. To provide molecular characteristics of human thyroid clockwork, primary thyrocytes established from normal or nodular thyroid tissue biopsies were subjected to in vitro synchronization with subsequent clock gene expression analysis by circadian bioluminescence reporter assay, and by quantitative RT-PCR.
Results: The expression levels of Bmal1 were up-regulated in tissue samples of Follicular Thyroid Carcinoma (FTC), and in Papillary Thyroid Carcinoma (PTC), as compared to normal thyroid and benign nodules, while Cry2 was down-regulated in FTC and PTC. Human thyrocytes derived from normal thyroid tissue exhibited high-amplitude circadian oscillations of Bmal1-luciferase reporter expression, and of endogenous clock transcripts. Thyrocytes established from FTC and PTC exhibited clock transcript oscillations similar to those of normal thyroid tissue and benign nodules (except for Per2 altered in PTC), while cells derived from Poorly Differentiated Thyroid Carcinoma (PDTC) exhibited altered circadian oscillations.
Conclusions: This is the first study demonstrating a molecular makeup of human thyroid circadian clock. Characterization of the thyroid clock machinery alterations upon thyroid nodule malignant transformation contributes to understanding the connections between circadian clocks and oncogenic transformation. Moreover, it might help improving the thyroid nodule pre-operative diagnostics.