Different expression of TSH receptor and NIS genes in thyroid cancer: role of epigenetics

Area of Science:

• Molecular Biology
• Oncology
• Endocrinology

Background:

• Differentiated thyroid cancers (DTCs) are often treated with radioiodine, targeting the sodium/iodide symporter (NIS) and TSH receptor (TSHR).
• NIS expression is frequently lost in DTCs, while TSHR is usually retained, complicating treatment efficacy.
• Understanding the regulation of NIS and TSHR gene expression is crucial for improving radioiodine therapy outcomes.

Purpose of the Study:

• To investigate the regulatory mechanisms of NIS and TSHR gene expression in thyroid tumor cells.
• To analyze the impact of inhibiting ras-BRAF-MAPK and PI3K-Akt-mTOR signaling pathways on NIS and TSHR expression.
• To explore the role of epigenetic modifications in controlling NIS and TSHR gene expression in thyroid cancer.

Main Methods:

• Quantitative real-time PCR (qPCR) to measure NIS and TSHR mRNA levels.
• Western blotting to assess total and phosphorylated ERK and Akt protein levels.
• Chromatin immunoprecipitation (ChIP) to investigate histone modifications at NIS and TSHR gene promoters.

Main Results:

• Inhibition of Akt signaling increased NIS mRNA and decreased TSHR mRNA in FTC-133 cells, with varied effects in BCPAP cells.
• Inhibition of ERK signaling upregulated both NIS and TSHR mRNA in BCPAP cells but not in FTC-133 cells.
• Epigenetic modifications at NIS and TSHR gene promoters exhibited cell- and gene-specific differences under basal conditions and after pathway inhibition.

Conclusions:

• TSHR and NIS gene expression in thyroid cancer cells is differentially regulated by multiple mechanisms.
• Major signaling pathways (MAPK, PI3K-Akt-mTOR) influence NIS and TSHR expression through epigenetic events.
• These findings highlight the complex regulatory network governing NIS and TSHR expression in thyroid tumorigenesis, impacting therapeutic strategies.