Thyroid hormone suppresses expression of stathmin and associated tumor growth in hepatocellular carcinoma.

Yi-Hsin Tseng,Sheng-Ming Wu,Ya-Hui Huang,Ming-Ming Tsai,Hsiang-Cheng Chi,Chung-Ying Tsai,Wei-Chun Chang,Yang-Hsiang Lin,Ya-Ting Chang,Wei-Jan Chen,Tzu-Kang Lin,Kwang-Huei Lin

doi:10.1038/srep38756

Yi-Hsin Tseng, Sheng-Ming Wu + Show 10 more

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https://doi.org/10.1038/srep38756

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Stathmin (STMN1), a recognized oncoprotein upregulated in various solid tumors, promotes microtubule disassembly and modulates tumor growth and migration activity. However, the mechanisms underlying the genetic regulation of STMN1 have yet to be elucidated. In the current study, we report that thyroid hormone receptor (THR) expression is negatively correlated with STMN1 expression in a subset of clinical hepatocellular carcinoma (HCC) specimens. We further identified the STMN1 gene as a target of thyroid hormone (T3) in the HepG2 hepatoma cell line. An analysis of STMN1 expression profile and mechanism of transcriptional regulation revealed that T3 significantly suppressed STMN1 mRNA and protein expression, and further showed that THR directly targeted the STMN1 upstream element to regulate STMN1 transcriptional activity. Specific knockdown of STMN1 suppressed cell proliferation and xenograft tumor growth in mice. In addition, T3 regulation of cell growth arrest and cell cycle distribution were attenuated by overexpression of STMN1. Our results suggest that the oncogene STMN1 is transcriptionally downregulated by T3 in the liver. This T3-mediated suppression of STMN1 supports the theory that T3 plays an inhibitory role in HCC tumor growth, and suggests that the lack of normal THR function leads to elevated STMN1 expression and malignant growth.

Highlights

Thyroxine, known as 3,3′,5-triiodo-L-thyronine (T3), mediates numerous physiological processes, including ontogenesis, cell growth, cellular differentiation and metabolism, in most mammalian tissues
thyroid hormone receptors (THRs) usually interact with retinoid X receptor (RXR) to form heterodimers that bind to thyroid hormone response elements (TREs) within the promoter regions or introns of target genes to regulate their transcriptional activity[3]
Several studies have confirmed that hypothyroidism triggers hyperlipidemia, obesity and non-alcoholic steatohepatitis, the latter of which progresses to liver cirrhosis and hepatocellular carcinoma (HCC) development[7,8]

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Known as 3,3′,5-triiodo-L-thyronine (T3), mediates numerous physiological processes, including ontogenesis, cell growth, cellular differentiation and metabolism, in most mammalian tissues. THRs play an important role in tumor progression, as evidenced by their aberrant expression and mutation in other human cancers, including pituitary tumors, thyroid papillary cancer and renal clear-cell carcinomas[16,17,18,19]. THRB overexpression potently represses tumor metastasis[22] These findings collectively suggest that loss of normal regulation of THRs enhances tumor progression, supporting a tumor-suppressor function of these receptors. STMN1 interacts with p27 and Cdk2/Cdk[5], leading to enhanced protein phosphorylation and consequent tubulin stabilization and inhibition of cell migration[36]. These findings support a crucial role of STMN1 in cancer growth and mobility

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