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Parallel Measurement of Circadian Clock Gene Expression and Hormone Secretion in Human Primary Cell Cultures
Published on: November 11, 2016
Identifying CSNK1E as a therapeutic target in thyroid cancer among the core circadian clock genes
Shun-Yu Chi1, Yi-Chiung Hsu2,3,4, Chung-Hsin Tsai5,6
1Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Abstract:
Previous studies have shown that thyroid malignancies can alter the transcriptional oscillations of circadian clock genes. In this study, we screened the expression of core circadian clock genes in thyroid neoplasms and found that CSNK1E, NPAS2, and TIMELESS were upregulated, while ARNTL, CRY1, CRY2, PER2, and RORA were downregulated during the progression and dedifferentiation of thyroid cancer. Immunohistochemical analysis further confirmed an increase in CSNK1E expression parallel to the loss of tumor differentiation. To investigate the potential therapeutic implications, we treated thyroid cancer cell lines with two different CSNK1E inhibitors: PF670462 and IC261. Both inhibitors resulted in growth inhibition in monolayer and three-dimensional spheroid cultures. This growth inhibition was accompanied by G2/M cell cycle arrest and a decrease in CDK4 and cyclin D1 expression. Moreover, CSNK1E inhibitors suppressed cell migration and invasion and reduced the expression of epithelial-mesenchymal transition markers. In vivo experiments using xenograft models showed that the administration of IC261 significantly restrained tumor growth and decreased the Ki-67 index of the xenograft tumors. In conclusion, our study provides evidence of aberrant CSNK1E expression in thyroid cancer dedifferentiation and highlights the potential therapeutic value of targeting CSNK1E.
Insights
Altered circadian clock gene expression, including increased CSNK1E, is linked to thyroid cancer progression. Targeting CSNK1E with inhibitors suppressed thyroid cancer cell growth and tumor development in preclinical models.
Area of Science:
- Molecular Biology
- Oncology
- Chronobiology
Background:
- Thyroid malignancies are associated with altered circadian clock gene transcription.
- Specific clock genes show differential expression during thyroid cancer progression and dedifferentiation.
Purpose of the Study:
- To investigate the expression patterns of core circadian clock genes in thyroid neoplasms.
- To evaluate the therapeutic potential of targeting casein kinase 1 epsilon (CSNK1E) in thyroid cancer.
Main Methods:
- Screening of core circadian clock gene expression in thyroid neoplasms.
- Immunohistochemical analysis of CSNK1E expression.
- In vitro treatment of thyroid cancer cell lines with CSNK1E inhibitors (PF670462, IC261).
- In vivo xenograft mouse models treated with IC261.
Main Results:
- CSNK1E, NPAS2, and TIMELESS were upregulated; ARNTL, CRY1, CRY2, PER2, and RORA were downregulated in thyroid cancer.
- Increased CSNK1E expression correlated with reduced tumor differentiation.
- CSNK1E inhibitors inhibited cell growth, induced G2/M cell cycle arrest, and suppressed migration and invasion.
- IC261 treatment significantly reduced tumor growth and proliferation in vivo.
Conclusions:
- Aberrant CSNK1E expression is implicated in thyroid cancer dedifferentiation.
- Targeting CSNK1E represents a promising therapeutic strategy for thyroid cancer.
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