Cathepsin H regulated by the thyroid hormone receptors associate with tumor invasion in human hepatoma cells

• Published in: Oncogene Vol. 30; no. 17; pp. 2057 - 2069
• Main Authors: Wu, S-M, Huang, Y-H, Yeh, C-T, Tsai, M-M, Liao, C-H, Cheng, W-L, Chen, W-J, Lin, K-H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.04.2011; Nature Publishing Group
• Subjects: 631/208/200; 631/80/84/2336; 692/420/755; 692/699/67/1504/1610; Analysis; Animals; Apoptosis; Base Sequence; Biological and medical sciences; Carcinogenesis; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cathepsin H; Cathepsin H - genetics; Cathepsin H - metabolism; Cathepsins; Cell activation; Cell adhesion & migration; Cell Biology; Cell differentiation; Cell migration; Cell Movement - drug effects; Cell physiology; Cell receptors; Cell structures and functions; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Colon cancer; Extracellular signal-regulated kinase; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Hep G2 Cells; Hepatocellular carcinoma; Hepatoma; Hormone receptors; Hormones; Human Genetics; Humans; Internal Medicine; Liver cancer; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Medicine; Medicine & Public Health; Metalloproteinase; Metastases; Metastasis; Mice; Microvasculature; Miscellaneous; Molecular and cellular biology; mRNA; Neoplasm Invasiveness - genetics; Nuclear receptors; Nucleotides; Oncology; original-article; Physiological aspects; Promoter Regions, Genetic - genetics; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Thyroid Hormone - metabolism; Retinoid X Receptors - metabolism; Risk factors; RNA, Messenger - genetics; RNA, Messenger - metabolism; Thyroid gland; Thyroid hormone receptors; Thyroid hormones; Transcription, Genetic - drug effects; Triiodothyronine; Triiodothyronine - pharmacology; Tumors; Up-Regulation - drug effects; Taiwan; migration; receptors; cysteine proteases; hepatocellular carcinoma; Human; Cysteine; Enzyme; Cysteine endopeptidases; Cathepsin H; Migration; Hepatic disease; Hepatocellular carcinoma; Malignant tumor; Metastasis; Carcinogenesis; Peptidases; Hydrolases; Digestive diseases; Thyroid hormone; Cancer; Biological receptor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.585

Thyroid hormone, 3, 3′, 5-triiodo- L -thyronine (T 3 ), mediates cell growth, development and differentiation by binding to its nuclear receptors (TRs). The role of TRs in cancer is still undefined. Notably, hyperthyroxinemia has been reported to influence the rate of colon cancer in an experimental model of carcinogenesis in rats. Previous microarray analysis revealed that cathepsin H (CTSH) is upregulated by T 3 in HepG2-TR cells. We verified that mRNA and protein expression of CTSH are induced by T 3 in HepG2-TR cells and in thyroidectomized rats following administration of T 3 . The possible thyroid hormone-responsive elements of the CTSH promoter localized to the nucleotides –2038 to –1966 and –1565 to –1501 regions. An in vitro functional assay showed that CTSH can increase metastasis. J7 cells overexpressing CTSH were inoculated into severe combined immune-deficient mice and these J7-CTSH mice displayed a greater metastatic potential than did J7-control mice. The clinicopathologic significance of CTSH expression in hepatocellular carcinoma (HCC) was also investigated. The CTSH overexpressing in HCC was associated with the presence of microvascular invasion ( P =0.037). The microvascular invasion characteristic is closely related to our in vitro characterization of CTSH function. Our results show that T 3 -mediated upregulation of CTSH led to matrix metallopeptidase or extracellular signal-regulated kinase activation and increased cell migration. This study demonstrated that CTSH overexpression in a subset hepatoma may be TR dependent and suggests that this overexpression has an important role in hepatoma progression.