Abstract
Thyroid hormone (T3) and its receptor (TR) are involved in cell metabolism and cancer progression. Hypothyroidism is associated with significantly elevated risk of hepatocellular carcinoma (HCC). Levels of the glycoprotein alpha-fetoprotein (AFP) are increased in the majority of patients with HCC and may be useful in diagnosis and follow-up. However, the relationship between T3/TR and AFP levels in HCC is currently unclear. The expression profiles of long non-coding RNAs (lncRNAs) were compared in microarrays of HepG2-TRα1 cells treated with/without T3 and HCC specimens. The effects of T3 on taurine upregulated gene 1 (TUG1) and AFP expression were validated using qRT-PCR. A correlation between TUG1 and AFP was confirmed via RNAi and clustered regularly interspaced short palindromic repeats (CRISPR) strategies. Finally, overall and recurrence-free survival rates were analyzed using the Kaplan–Meier method and confirmed in online datasets. T3/TR treatment reduced TUG1 expression in vitro, resulting in the downregulation of AFP mRNA. Knockdown of TUG1 suppressed cell cycle progression and soft agar colony formation and induced cellular senescence. Our data support the involvement of TUG1 in the T3/TR-mediated suppression of cell growth. AFP mRNA levels showed strong positive correlations with TUG1 and unfavorable prognosis in patients with non-hepatitis B/non-hepatitis C HCC (NBNC-HCC). T3/TR, TUG1, and AFP may potentially serve as effective prognostic markers for NBNC-HCC.
Highlights
Thyroid hormone (3,30,5-triiodo-l-thyronine; T3 ) regulates cell homeostasis, growth, development, autophagy and metabolism [1] through binding to thyroid hormone receptors (TR) [2]
Among the candidate long non-coding RNAs (lncRNAs) simultaneously downregulated by T3 /TR and upregulated in hepatocellular carcinoma (HCC)
The present study showed that T3 /TR downregulates taurine upregulated gene 1 (TUG1) and AFP mRNA and protein levels, correlation between TUG1 and AFP expression was evident in the NBNC group (Figure 5B)
Summary
Thyroid hormone (3,30 ,5-triiodo-l-thyronine; T3 ) regulates cell homeostasis, growth, development, autophagy and metabolism [1] through binding to thyroid hormone receptors (TR) [2]. Aberrant expression and/or mutation of TRs has been documented in pituitary tumors [4], hepatocellular carcinoma (HCC) [5] and thyroid cancer [6]. Cells 2020, 9, 262 elevated risk for HCC, especially in hepatitis virus-negative subjects, non-drinkers, non-diabetics and non-smokers [7], along with non-alcoholic steatohepatitis (NASH) [8]. These findings indicate that T3 /TR acts to suppress the development of liver cancer. The molecular mechanisms underlying the associations between T3 /TR and HCC are yet to be elucidated
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