Abstract
Epigenetic modifications have been identified as being responsible for the de-differentiation of thyroid tissue and its malignant transformation. Cell proliferation inhibitory effects of the pan-deacetylase inhibitors panobinostat, SAHA and Trichostatin A (TSA), the modulation of the sodium iodide symporter (NIS; SLC5A5), thyroid transcription factor 1 (TTF1), high mobility group A2 (HMGA2), and H19 and their putative targeting miRNAs have been evaluated in vitro. The cell viability was measured in five thyroid cancer cell lines (FTC133, TPC1, BCPAP, 8505C, C643) by real time cell analyzer xCELLigence. Expression of the above mentioned markers was performed by RT-qPCR and Western Blot. Radioiodine up-take was detected by Gamma Counter with I131. Cell viability decreased after treatment in all five cell lines. 10 nM panobinostat; 1 µM TSA or 10 µM SAHA caused a significant over-expression of NIS transcript in all five cell lines, whereas NIS protein was up-regulated in FTC133, BCPAP, and C643 cell lines only. Radioiodine up-take increased in FTC133 and C643 cells after 48 h of treatment with 10 nM panobinostat and 1 µM TSA. A significant down-regulation of the oncogene HMGA2 was detected in all five cell lines; except for TPC1 cells that were treated with 1 µM TSA. In accordance, hsa-let-7b-5p and hsa-let-7f-5p were stable or significantly over-expressed in all of the cell lines, except for TPC1 cells that were treated with 10 µM SAHA. TTF1 was significantly down-regulated in FTC133, BCPAP, and 8505C cells; whereas, TPC1 and C643 showed an up-regulated or stable expression. TTF1 was over-expressed in samples of human anaplastic thyroid cancer; whereas, it was down-regulated in follicular and undetectable in papillary thyroid cancer. H19 was over-expressed after 48 h treatment, except for BCPAP cells that were treated with panobinostat and SAHA. H19 was differently expressed in human anaplastic, follicular and papillary thyroid tumor samples. Deacetylase inhibitors reduced cell viability, restored NIS and H19, and suppressed the oncogenes HMGA2 and TTF1 in thyroid cancer cells.
Highlights
Thyroid cancer is the most common endocrine malignancy and its incidence is increasing worldwide every year
The resistance to radioiodine in PDTC as well as in anaplastic thyroid cancer (ATC) is caused by a dysfunction of the sodium-iodide symporter (NIS; SLC5A5)
This study aimed to clarify the mechanisms induced by Histone deacetylase inhibitors (HDACi) in in vitro models of thyroid cancer, highlighting the ability of these compounds to induce re-differentiation in thyroid cancer cell lines via the over-expression of NIS, the modulation of the long non-coding RNA H19, and the suppression of oncogenes, like transcription factor 1 (TTF1) and high mobility group A2 (HMGA2)
Summary
Thyroid cancer is the most common endocrine malignancy and its incidence is increasing worldwide every year. The resistance to radioiodine in PDTC as well as in ATC is caused by a dysfunction of the sodium-iodide symporter (NIS; SLC5A5). This dysfunction is mainly due to suppression, loss of NIS gene [2,3], and/or a distorted alignment at the cytosolic membrane site [4]. NIS transcript and protein level have been shown to be low in undifferentiated thyroid cancer, the re-expression of NIS gene could restore the radioiodine up-take [5]. The expression of hsa-let-7f-5p and hsa-let-7b-5p is significantly high in patients that are affected by thyroid cancer and this is correlated with the strong down-regulation of NIS mRNA [6]
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