Endocrine Abstracts

Introduction: Studies suggest that disturbed thyroid hormones (TH) homeostasis may lead to increased cancer risk. However, the exact role of TH in cancerogenesis is unknown. We have previously identified 15 genes linked with TH signaling in 7 cancer types and 10.967 cancer patients. Here, we investigated the influence of hypothyroidism on the expression of these 15 genes in rat tissues/organs from which the previously identified, TH-related cancer types originate.

Material and Methods: Female Wistar-Kyoto rats were divided into 3 groups: i) treated with methimazole (MMI) (17 mg/kg daily for 8 weeks); ii)thyroidectomized;iii) control rats. n = 3 rats per group. Gene expression was analyzed (qPCR) in: mammary glands, renal cortex, lungs, thyroid gland, endometrium, liver, ovary, and colon epithelium. Statistical analysis: Student’s unpaired t-test, P-values <0.05 were considered significantly different. PanCancer analysis of co-expression of genes encoding mesenchymal stem cells (MSC) markers and genes linked to TH signaling was performed using publically available TCGA data from 10.967 cancer patients. The study was approved by the local ethics committee (Second Warsaw Local Ethics Committee for Animal Experimentation) no. WAW2/022/2018.

Results: The induction of hypothyroidism in rats was confirmed by serum evaluation of T4 (avg. 0.60 µg/dl) and TSH (avg. 20.23 ng/ml). In mammary and thyroid glands of MMI treated rats, strong induction of analyzed genes expression was observed, including ARNT, THRA, THRB, SLC16A2, SLC2A1, CTNNB1, NCOA1, HDAC1, CMYC, HIF1A upregulated in both tissues, and VIM, CDH1 and TPOupregulated only in thyroid glands. In the residual MMI-treated tissue types the only significant expression changes were: HDAC1downregulation in renal cortex and lungs, DIO2 downregulation in endometrium, and THRA upregulation in colon epithelium. Expression profile in mammary glands ofthyroidectomized rats did not confirm induction of gene expression observed in MMI treated rats. Results of PanCancer TCGA data analysis revealed associations between expressions of genes linked with TH signaling and MSC functioning, including THY1/RCAN2 and ENG/RCAN2 which occurred in 11 cancer types.

Discussion: The study suggests that observed expression changes in mammary and thyroid glands are caused not only by hypothyroidism but also by MMI influence on these tissues. Elucidation of the observed expression changes requires further research. Since MMI, apart from TPO, can interact with other peroxidases like MPO, EPO and LPO,this interaction may lead to decreased selectivity of MMI inhibition and cause broader impact on gene expression.

Supported by grants: 501-1-25-01-19 and 2018/29/B/NZ5/01 211 (National Science Center, Poland).