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

Abstract

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.

Molecular functions and clinical impact of thyroid hormone-triggered autophagy in liver-related diseases

“…For instance, administration of TH not only reduces the size of preneoplastic lesions in the livers of rats suffering with HCC, but suppresses the aberrant cellular growth via control the expression of cell cycle regulators, such as CDK2, Cyclin E, UHRF1, STMN1 mir-214 and BC200 lncRNA [7,[171][172][173][174]. Our recent studies further support the preventive effect of TH on hepatocarcinogenesis via activating autophagy [16,17], whereas TH/THR is reported to promote metastasis and chemoresistance through control the expressions of BSSP4, TRAIL, BCL2L11, LCN2, mir-21, and mir-130b [7,173,[175][176][177][178][179][180]. This characteristic of THs supports the double-edged sword effect of autophagy in cancer progression.…”

“…Significant links between the regulation of selective autophagy and liver complications associated with NAFLD and HCC have been reported, supporting the manipulation of this process as a potential therapeutic strategy for liver-related diseases. Apoptosis regulator TRAIL [175] Metastatic regulator BSSP4 [178] LCN2 [180] mir-130b [177] mir-21 [179] Autophagy in liver-related diseases…”

Triiodothyronine stimulates VEGF expression and secretion via steroids and HIF-1α in murine Leydig cells

“…Thyroid hormone, 3, 5, 3ʹ-L-triiodothyronine (T 3 ) has been shown to increase basal and cAMP-stimulated steroid production in primary Leydig cells and their derived lines (Manna et al 1999(Manna et al , 2001Maran et al 2000). T 3 also stimulates VEGF mRNA and protein levels in a variety of other cell lines including rat brain-derived endothelial cells and human hepatoma cells (Zhang et al 2010;Chen et al 2014). Hyperthyroid patients also have higher serum VEGF levels (Iitaka et al 1998).…”

Dual inhibition of histone deacetylases and phosphoinositide 3-kinases: effects on Burkitt lymphoma cell growth and migration

“…The inhibition of PI3K/Akt and ERK1/2 has been reported to reduce cell migration and induce cell death in solid tumors, such as small cell lung cancer, hepatoma, and NHL [43][44][45]. Most BL cell lines have constitutively high levels of PI3K activity.…”