SEPHS1 promotes SMAD2/3/4 expression and hepatocellular carcinoma cells invasion

Shu Yang,Ting Luo,Hui Hua,Yangfu Jiang,Jin Zhang,Hua Yang,Hongying Zhang,Jiao Wang

doi:10.1186/s40164-021-00212-7

Abstract

BackgroundHepatocellular carcinoma (HCC) is one of the common cancers that are very aggressive. The secreted cytokine transforming growth factor-β (TGF-β) promotes cancer metastasis by multiple mechanisms such as epithelial-mesenchymal transition and immune evasion. The canonical TGF-β signaling is largely mediated by smooth muscle actin/mothers against decapentaplegic (SMAD) proteins. The current study aims to explore the regulation of TGF-β/SMAD signaling by selenophosphate synthetase 1 (SEPHS1).MethodsImmunohistochemistry was used to detect the expression of SEPHS1 in HCC and adjacent liver tissues. Western blotting and quantitative reverse-transcription PCR were used to detect the protein and mRNA levels in HCC cell lines. Cell migration and invasion were determined by transwell assay. Bioinformatic analysis was conducted to determine SEPHS1 expression in HCC and its correlation with the survival of HCC patients.ResultsHere we report that SEPHS1 is a positive regulator of SMAD proteins. SEPHS1 expression is up-regulated in HCC compared with adjacent liver tissues. SEPHS1 knockdown leads to decreased expression of SMAD2/3/4 and mesenchymal markers including snail, slug and N-cadherin in HCC cells. Furthermore, SEPHS1 knockdown results in a decrease in HCC cells migration and invasion, and suppresses the stimulation of HCC cells migration and invasion by TGF-β. Overexpression of SEPHS1 in HCC cells promotes cell invasion, which can be abrogated by SMAD3 knockdown. Lastly, higher expression of SEPHS1 is correlated with poor prognosis in HCC patients, as manifested by decreased overall survival and disease-free survival.ConclusionsSEPHS1 is a positive regulator of TGF-β/SMAD signaling that is up-regulated in HCC. Increased SEPHS1 expression may indicate poor prognosis for patients with HCC.

Highlights

Hepatocellular carcinoma (HCC) is one of the common cancers that are very aggressive
By comparing the mRNA levels of selenophosphate synthetase 1 (SEPHS1) in normal livers and HCC in the Roessier Liver dataset, we found that the levels of SEPHS1 in HCC were increased in HCC (Fig. 1a)
Data from the HCC cohort in the Cancer Genome Atlas (TCGA) database revealed that SEPHS1 is overexpressed in HCC (Fig. 1b)

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the common cancers that are very aggressive. The secreted cytokine transforming growth factor-β (TGF-β) promotes cancer metastasis by multiple mechanisms such as epithelial-mesenchymal transition and immune evasion. Yang et al Exp Hematol Oncol (2021) 10:17 drivers are enriched in multiple pathways such as cell cycle, Wnt signaling, transforming growth factor-β (TGF-β) signaling and JAK-STAT signaling [7]. TGF-β is a pleiotropic growth factor that has diverse roles in epithelial-mesenchymal transition (EMT), development, carcinogenesis, cancer metastasis and immune escape [8,9,10,11]. The canonical TGF-β singaling is mediated by SMADs. Upon TGF-β binding to its receptor complex including type I and type II TGF-β receptors (TGFBR1 and TGFBR2), TGFBR is phoshorylated and activated, and induces SMAD2/3 phosphorylation. Given the importance of TGF-β signaling in tumorigenesis, it is crutial to identify the regulators of TGF-β signaling that are aberrantly expressed in human cancer

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Conclusion