Molecular insights into the transcriptional regulatory role of thyroid hormones in ovarian cancer

Abstract

The regulation of cancer-relevant genes by the thyroid hormones, 3, 5, 3′-Triiodo-Lthyronine (T3) and L-thyroxine (T4), was recently acknowledged. However, limited data exists on the hormonal effects on gene expression in ovarian cancer, a gynecological malignancy associated with a low cure rate. The expression of fifteen genes involved in DNA repair, cell cycle, apoptosis, and tumor suppression was evaluated in OVCAR-3 and A2780 cell lines, using real-time PCR following short incubation with T3 (1 nM) or T4 (100 nM). The thyroid hormones downregulated the expression of the majority of genes examined. Support for the involvement of the MAPK and PI3K in thyroid hormone-mediated gene expression was shown for a set of genes. FAS expression was inhibited in A2780 cells, while an unexpected induction was demonstrated in OVCAR-3 cells. An analogous effect on the protein levels of FAS receptor and its soluble form was demonstrated by Western blotting. We further established, using primer sets that discriminate between the different RNA isoforms, that the hormones increase the mRNA levels of both coding and non-coding FAS mRNAs. The prevalence of these isoforms, using The Cancer Genome Atlas (TCGA) analysis, was significantly more abundant in 17 cancer types, including ovarian cancer, compared to normal tissues. Our results highlight the role of thyroid hormones in the expression of cancer-relevant-genes in ovarian cancer and provide an important insight into the pathways by which mitogenic and anti-apoptotic effects are exerted. This integrin contains an Arg-Gly-Asp (RGD) recognition site that binds extra cellular matrix (ECM) proteins containing this sequence. At close proximity to the RGD recognition site, a thyroid hormone receptor was described. 1,2 The receptor is complex and includes a site for T3 and a second site for T3 and for L-thyroxine (T4), 3 the principal secretory product of the thyroid gland. Physiological levels of T4 activate the thyroid hormone receptor on αvβ3, whereas supraphysiologic concentrations of T3 are required to achieve stimulation at this Molecular Carcinogenesis. 2018;57:97-105.wileyonlinelibrary.com/journal/mc

Cytoplasmic versus nuclear THR alpha expression determines survival of ovarian cancer patients

“…The same group studied the expression of fifteen genes involved in DNA repair, cell cycle, apoptosis, and tumor suppression in OVCAR-3 and A2780 cell lines, using real-time PCR following short incubation with T3 or T4 (Shinderman-Maman et al 2018). The thyroid hormones downregulated the expression of the majority of genes examined, showing that these hormones influence the expression of cancerrelevant genes in ovarian cancer (Shinderman-Maman et al 2018). The same group hypothesized that natural thyroid hormone derivatives may antagonize these actions.…”

THR alpha and its subtypes alpha1 and alpha2 are prognostic markers for survival of ovarian cancer patients

“…Both hormones induced cell proliferation and significantly reduced the expression of genes that inhibit cell cycle particularly in ovarian cancer cells (OVCAR-3) with high integrin expression [18]. The same group studied the expression of fifteen genes involved in DNA repair, cell cycle, apoptosis, and tumor suppression in OVCAR-3 and A2780 cell lines, using real-time PCR following short incubation with T3 or T4 [38]. The thyroid hormones downregulated the expression of the majority of genes examined, showing that these hormones influence the expression of cancer-relevant-genes in ovarian cancer [38].…”

“…The same group studied the expression of fifteen genes involved in DNA repair, cell cycle, apoptosis, and tumor suppression in OVCAR-3 and A2780 cell lines, using real-time PCR following short incubation with T3 or T4 [38]. The thyroid hormones downregulated the expression of the majority of genes examined, showing that these hormones influence the expression of cancer-relevant-genes in ovarian cancer [38]. The same group hypothesized that natural thyroid hormone derivatives may antagonize these actions.…”

Triiodothyronine lowers the potential of colorectal cancer stem cells in vitro

“…The cells maintained in the SCM without T3 were used as control cells. Initially, T3 concentrations for the present study were established according to literature data (0.5, 1 or 2 nM) (13)(14)(15)(16). Our first analyses indicated that T3 in concentrations higher than 1 nM causes cell death, thus if a selection had to be made lower T3 concentrations (0.5 or 1 nM) were used.…”