Thyroid hormone enhanced human hepatoma cell motility involves brain-specific serine protease 4 activation via ERK signaling

Cheng Yi Chen, I. Hsiao Chung, Ming Ming Tsai, Yi Hsin Tseng, Hsiang Cheng Chi, Chung Ying Tsai, Yang Hsiang Lin, You Ching Wang, Chie Pein Chen, Tzu I. Wu, Chau Ting Yeh, Dar In Tai, Kwang Huei Lin

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: The thyroid hormone, 3, 3′, 5-triiodo-L-thyronine (T3), has been shown to modulate cellular processes via interactions with thyroid hormone receptors (TRs), but the secretory proteins that are regulated to exert these effects remain to be characterized. Brain-specific serine protease 4 (BSSP4), a member of the human serine protease family, participates in extracellular matrix remodeling. However, the physiological role and underlying mechanism of T3-mediated regulation of BSSP4 in hepatocellular carcinogenesis are yet to be established.Methods: The thyroid hormone response element was identified by reporter and chromatin immunoprecipitation assays. The cell motility was analyzed via transwell and SCID mice. The BSSP4 expression in clinical specimens was examined by Western blot and quantitative reverse transcription polymerase chain reaction.Results: Upregulation of BSSP4 at mRNA and protein levels after T3 stimulation is a time- and dose-dependent manner in hepatoma cell lines. Additionally, the regulatory region of the BSSP4 promoter stimulated by T3 was identified at positions -609/-594. BSSP4 overexpression enhanced tumor cell migration and invasion, both in vitro and in vivo. Subsequently, BSSP4-induced migration occurs through the ERK 1/2-C/EBPβ-VEGF cascade, similar to that observed in HepG2-TRα1 and J7-TRα1 cells. BSSP4 was overexpressed in clinical hepatocellular carcinoma (HCC) patients, compared with normal subjects, and positively associated with TRα1 and VEGF to a significant extent. Importantly, a mild association between BSSP4 expression and distant metastasis was observed.Conclusions: Our findings collectively support a potential role of T3 in cancer cell progression through regulation of the BSSP4 protease via the ERK 1/2-C/EBPβ-VEGF cascade. BSSP4 may thus be effectively utilized as a novel marker and anti-cancer therapeutic target in HCC.

Original languageEnglish
Article number162
JournalMolecular Cancer
Volume13
Issue number1
DOIs
Publication statusPublished - Jul 1 2014
Externally publishedYes

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Serine Proteases
Thyroid Hormones
Cell Movement
Hepatocellular Carcinoma
Brain
Vascular Endothelial Growth Factor A
Thyronines
Thyroid Hormone Receptors
Neoplasms
SCID Mice
Chromatin Immunoprecipitation
Nucleic Acid Regulatory Sequences
Response Elements
Reverse Transcription
Extracellular Matrix
Carcinogenesis
Proteins
Peptide Hydrolases
Up-Regulation
Western Blotting

Keywords

  • BSSP4
  • ERK 1/2-C/EBPβ-VEGF
  • Mmotility
  • Secreted protein
  • SILAC
  • Thyroid hormone receptor

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Oncology
  • Medicine(all)

Cite this

Chen, C. Y., Chung, I. H., Tsai, M. M., Tseng, Y. H., Chi, H. C., Tsai, C. Y., ... Lin, K. H. (2014). Thyroid hormone enhanced human hepatoma cell motility involves brain-specific serine protease 4 activation via ERK signaling. Molecular Cancer, 13(1), [162]. https://doi.org/10.1186/1476-4598-13-162

Thyroid hormone enhanced human hepatoma cell motility involves brain-specific serine protease 4 activation via ERK signaling. / Chen, Cheng Yi; Chung, I. Hsiao; Tsai, Ming Ming; Tseng, Yi Hsin; Chi, Hsiang Cheng; Tsai, Chung Ying; Lin, Yang Hsiang; Wang, You Ching; Chen, Chie Pein; Wu, Tzu I.; Yeh, Chau Ting; Tai, Dar In; Lin, Kwang Huei.

In: Molecular Cancer, Vol. 13, No. 1, 162, 01.07.2014.

Research output: Contribution to journalArticle

Chen, CY, Chung, IH, Tsai, MM, Tseng, YH, Chi, HC, Tsai, CY, Lin, YH, Wang, YC, Chen, CP, Wu, TI, Yeh, CT, Tai, DI & Lin, KH 2014, 'Thyroid hormone enhanced human hepatoma cell motility involves brain-specific serine protease 4 activation via ERK signaling', Molecular Cancer, vol. 13, no. 1, 162. https://doi.org/10.1186/1476-4598-13-162
Chen, Cheng Yi ; Chung, I. Hsiao ; Tsai, Ming Ming ; Tseng, Yi Hsin ; Chi, Hsiang Cheng ; Tsai, Chung Ying ; Lin, Yang Hsiang ; Wang, You Ching ; Chen, Chie Pein ; Wu, Tzu I. ; Yeh, Chau Ting ; Tai, Dar In ; Lin, Kwang Huei. / Thyroid hormone enhanced human hepatoma cell motility involves brain-specific serine protease 4 activation via ERK signaling. In: Molecular Cancer. 2014 ; Vol. 13, No. 1.
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AU - Tseng, Yi Hsin

AU - Chi, Hsiang Cheng

AU - Tsai, Chung Ying

AU - Lin, Yang Hsiang

AU - Wang, You Ching

AU - Chen, Chie Pein

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AU - Yeh, Chau Ting

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