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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, vol. 98, no. 11, pp. 4446-4456, November 2013.


Context: The 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 the 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 the Bmal1 were up-regulated in tissue samples of follicular thyroid carcinoma (FTC), and in papillary thyroid carcinoma (PTC), as compared with normal thyroid and benign nodules, whereas Cry2 was down-regulated in FTCandPTC. Human thyrocytes derived from normal thyroid tissue exhibited high-amplitude circadian oscillations of Bmal1-luciferase reporter expression and 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), whereas cells derived from poorly differentiated thyroid carcinoma exhibited altered circadian oscillations.

Conclusions: This is the first study demonstrating a molecular makeup of the 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 in improving the thyroid nodule preoperative diagnostics.

@ARTICLE(http://bigwww.epfl.ch/publications/mannic1302.html,
AUTHOR="Mannic, T. and Meyer, P. and Triponez, F. and Pusztaszeri, M.
	and Le Martelot, G. and Mariani, O. and Schmitter, D. and Sage, D.
	and Philippe, J. and Dibner, C.",
TITLE="Circadian Clock Characteristics Are Altered in Human Thyroid
	Malignant Nodules",
JOURNAL="The Journal of Clinical Endocrinology \& Metabolism",
YEAR="2013",
volume="98",
number="11",
pages="4446--4456",
month="November",
note="")

© 2013 The Endocrine Society. Personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution to servers or lists, or to reuse any copyrighted component of this work in other works must be obtained from The Endocrine Society. This material is presented to ensure timely dissemination of scholarly and technical work. Copyright and all rights therein are retained by authors or by other copyright holders. All persons copying this information are expected to adhere to the terms and constraints invoked by each author's copyright. In most cases, these works may not be reposted without the explicit permission of the copyright holder.
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