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Molecular Cancer

, 13:162

First Online: 01 July 2014Received: 17 December 2013Accepted: 19 June 2014DOI: 10.1186-1476-4598-13-162

Cite this article as: Chen, CY., Chung, IH., Tsai, MM. et al. Mol Cancer 2014 13: 162. doi:10.1186-1476-4598-13-162


BackgroundThe 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.

MethodsThe 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.

ResultsUpregulation 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.

ConclusionsOur 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.

KeywordsThyroid hormone receptor Secreted protein BSSP4 SILAC ERK 1-2-C-EBPβ-VEGF Mmotility AbbreviationsBSSP4Brain-specific serine protease 4

C-EBPβCCAAT-enhancer-binding protein β

ERKExtracellular signal-regulated kinase

HCCHepatocellular carcinoma

MAPKMitogen-activated protein kinase

THThyroid hormone

TREsThyroid hormone response elements

uPAurokinase-type plasminogen activator

VEGFVascular endothelial growth factor.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-13-162 contains supplementary material, which is available to authorized users.

Cheng-Yi Chen, I-Hsiao Chung contributed equally to this work.

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Autor: Cheng-Yi Chen - I-Hsiao Chung - Ming-Ming Tsai - Yi-Hsin Tseng - Hsiang-Cheng Chi - Chung-Ying Tsai - Yang-Hsiang Lin - You


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