Abstract
Thyroid hormone (TH) plays a role in regulating the metabolic rate, heart functions, muscle control and maintenance of bones. 3,3′5-tri-iodo-L-thyronine (T3) displays high affinity to nuclear thyroid hormone receptors (TRs), which mediate most TH actions. Recent studies have shown hypothyroidism in patients with an increased risk of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs), a class of non-protein-coding RNA, are suggested to control tumor growth by interacting with target genes. However, the clinical significance of T3/TR-regulated miRNAs in tumors has yet to be established. In the current study, miRNA expression profile screening was performed using SYBR Green-Based qRT-PCR array in TR-overexpressing HepG2 cells. miR-214-3p, which is expressed at low levels in HCC, was stimulated upon T3 application. The 3′UTR luciferase reporter assay confirmed that the proto-oncogene serine/threonine-protein kinase, PIM-1, is a miR-214-3p target. PIM-1 was decreased upon treatment with miR-214-3p or T3 stimulation. PIM-1 was highly expressed in HCC, and the effect of PIM-1 on cell proliferation might be mediated by the inhibition of p21. Furthermore, the T3-induced suppression of cell proliferation was partially rescued upon miR-214-3p knockdown. Our data demonstrate that T3 induces miR-214-3p expression and suppresses cell proliferation through PIM-1, thus contributing to the inhibition of HCC tumor formation.
Highlights
Thyroid hormone, 3,3′,5-tri-iodo-L-thyronine (T3) is a potent mediator of several physiological processes, including embryonic development, cellular differentiation, metabolism and cell growth
Results miR-214 is upregulated by T3. miR-214 was selected for study to demonstrate the potential suppressive role of the thyroid hormone receptors (TRs) in view of its downregulation in hepatocellular carcinoma (HCC) and positive regulation by T3/TR
To further ascertain whether T3/TRs upregulates miR-214 expression in HepG2-TR cells, experiments were performed at various time periods or T3 doses
Summary
3,3′,5-tri-iodo-L-thyronine (T3) is a potent mediator of several physiological processes, including embryonic development, cellular differentiation, metabolism and cell growth. T3 and the TRs regulate gene transcription by binding the thyroid hormone response elements (TREs), which are located in the upstream promoter regions of the target genes. Data from animal models and epidemiologic studies indicate an association between higher thyroid hormone levels and the prevention of liver diseases[5,6]. MiR-214 inhibits angiogenesis via the suppression of the target gene-HDGF in HCC and is associated with tumor progression and clinical outcome[20]. Data obtained from clinical studies confirm high expression levels of PIM-1 and support its utility as a prognostic biomarker in prostate cancer, oral cancer, colon cancer, head-and-neck squamous cell carcinoma, and gastric cancer[25,26,27,28,29]. The mechanisms underlying PIM-1 signaling in HCC remain to be established[30,31,32,33,34]
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