title: Thyroid hormone enhanced human hepatoma cell motility involves brain-specific serine protease 4 activation via ERK signaling.
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.
authors: Cheng-Yi
authors: CY
authors: Chen
authors: I-Hsiao
authors: IH
authors: Chung
authors: Ming-Ming
authors: MM
authors: Tsai
authors: Yi-Hsin
authors: YH
authors: Tseng
authors: Hsiang-Cheng
authors: HC
authors: Chi
authors: Chung-Ying
authors: CY
authors: Tsai
authors: Yang-Hsiang
authors: YH
authors: Lin
authors: You-Ching
authors: YC
authors: Wang
authors: Chie-Pein
authors: CP
authors: Chen
authors: Tzu-I
authors: TI
authors: Wu
authors: Chau-Ting
authors: CT
authors: Yeh
authors: Dar-In
authors: DI
authors: Tai
authors: Department of Biochemistry, School of Medicine, Chang-Gung University, 259 Wen-hwa 1 Road, Taoyuan, Taiwan. khlin@mail.cgu.edu.tw.
authors: Kwang-Huei
authors: KH
authors: Lin
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D011401:Promoter Regions, Genetic; D011988:Receptors, Thyroid Hormone / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013963:Thyroid Hormones / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D012697:Serine Endopeptidases; C500893:PRSS22 protein, human