14-3-3σ induces heat shock protein 70 expression in hepatocellular carcinoma.

Chia-Chia Liu,Song-Kun Shyue,Yee-Jee Jan,Li-Ying Sung,Yao-Ming Wu,John Wang,Jun-Yang Liou,Shu-Man Liang,Shyh-Chang Chen,Tzu-Ching Chang,Bor-Sheng Ko,Tzu-An Liu,Yen-Ming Lee

doi:10.1186/1471-2407-14-425

Abstract

Background14-3-3σ is implicated in promoting tumor development of various malignancies. However, the clinical relevance of 14-3-3σ in hepatocellular carcinoma (HCC) tumor progression and modulation and pathway elucidation remain unclear.MethodsWe investigated 14-3-3σ expression in 109 HCC tissues by immunohistochemistry. Overexpression and knockdown experiments were performed by transfection with cDNA or siRNA. Protein expression and cell migration were determined by Western blot and Boyden chamber assay.ResultsIn this study, we found that 14-3-3σ is abundantly expressed in HCC tumors. Stable or transient overexpression of 14-3-3σ induces the expression of heat shock factor-1α (HSF-1α) and heat shock protein 70 (HSP70) in HCC cells. Moreover, expression of 14-3-3σ significantly correlates with HSF-1α/HSP70 in HCC tumors and both 14-3-3σ and HSP70 overexpression are associated with micro-vascular thrombi in HCC patients, suggesting that 14-3-3σ/HSP70 expression is potentially involved in cell migration/invasion. Results of an in vitro migration assay indicate that 14-3-3σ promotes cell migration and that 14-3-3σ-induced cell migration is impaired by siRNA knockdown of HSP70. Finally, 14-3-3σ-induced HSF-1α/HSP70 expression is abolished by the knockdown of β-catenin or activation of GSK-3β.ConclusionsOur findings indicate that 14-3-3σ participates in promoting HCC cell migration and tumor development via β-catenin/HSF-1α/HSP70 pathway regulation. Thus, 14-3-3σ alone or combined with HSP70 are potential prognostic biomarkers for HCC.

Highlights

The 14-3-3 family of proteins regulates multiple cellular processes with a highly conserved homology among all eukaryotic cells [1,2]
14-3-3σ upregulates heat shock factor-1 (HSF-1) and heat shock protein 70 (HSP70) expression in hepatocellular carcinoma (HCC) To investigate the role of 14-3-3σ on HCC tumor progression, we examined the expression level of 14-3-3σ in HCC cell lines including Huh-7, HepG2, Hep3B, SK-Hep1 and PLC-5
To examine whether 14-3-3σ regulates HCC growth, the cell proliferation rate was determined by an MTT assay. 14-3-3σ overexpression has no significant effect on cell proliferation in comparison to the control cells (Figure 1C)

Summary

Introduction

The 14-3-3 family of proteins regulates multiple cellular processes with a highly conserved homology among all eukaryotic cells [1,2]. Epigenetic silencing of the 14-3-3σ (SFN) gene via CpG methylation has been reported in various cancer cells, including: breast, lung, liver, gastric cancer, ovarian and Several molecular markers, including heat shock protein 70 (HSP70), glypican 3 (GPC3) and glutamine synthetase (GS) were proposed as diagnostic markers of hepatocellular nodules in cirrhosis and early HCC [18,19,20,21,22,23,24]. Among these potential diagnostic factors, HSP70 is considered as a drug target for cancer therapy [25,26]. Accumulation or mutations of β-catenin increase cell proliferation and are associated with tumor progression in HCC [34,35,36,37]

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