Nemopilema nomurai jellyfish venom exerts an anti-metastatic effect by inhibiting Smad- and NF-\u03baB-mediated epithelial\u2013mesenchymal transition in HepG2 cells

Hyunkyoung Lee,Euikyung Kim,Jinho Chae,Hyeryeon Yang,Je-Hein Kim,Min Jung Pyo,Seong Kyeong Bae,Seungshic Yum,Indu Choudhary,Changkeun Kang,Duhyeon Hwang,Chang Hoon Han,Yunwi Heo

doi:10.1038/s41598-018-20724-3

Abstract

Epithelial–mesenchymal transition (EMT) is a key initial step in metastasis for malignant cancer cells to obtain invasive and motile properties. Inhibiting EMT has become a new strategy for cancer therapy. In our previous in vivo study, Nemopilema nomurai jellyfish venom (NnV) -treated HepG2 xenograft mice group showed that E-cadherin expression was strongly detected compared with non-treated groups. Therefore, this study aimed to determine whether NnV could inhibit the invasive and migratory abilities of HepG2 human hepatocellular carcinoma cells and to examine its effect on EMT. Our results revealed that transforming growth factor (TGF)-β1 induced cell morphological changes and downregulated E-cadherin and β-catenin expression, but upregulated N-cadherin and vimentin expression through the Smad and NF-κB pathways in HepG2 cells. Treatment of TGF-β1-stimulated HepG2 cells with NnV reversed the EMT-related marker expression, thereby inhibiting cell migration and invasion. NnV also significantly suppressed the activation of p-Smad3, Smad4, and p-NF-κB in a dose-dependent manner. These data indicated that NnV can significantly suppress cell migration and invasion by inhibiting EMT in HepG2 cells, and therefore might be a promising target for hepatocellular carcinoma therapeutics.

Highlights

Epithelial–mesenchymal transition (EMT) is a key initial step in metastasis for malignant cancer cells to obtain invasive and motile properties
The results revealed that Nemopilema nomurai jellyfish venom (NnV) at 0.6 μg/ml slightly inhibited the proliferation of HepG2 cells, whereas 0.2 and 0.4 μg/ml NnV had no significant effect (Fig. 1A)
As EMT is a key step in metastasis that initiates cancer cell migration, the migration potential of NnV-treated HepG2 cells was examined using wound-healing and transwell invasion assays

Summary

Introduction

Epithelial–mesenchymal transition (EMT) is a key initial step in metastasis for malignant cancer cells to obtain invasive and motile properties. NnV significantly suppressed the activation of p-Smad[3], Smad[4], and p-NF-κB in a dose-dependent manner These data indicated that NnV can significantly suppress cell migration and invasion by inhibiting EMT in HepG2 cells, and might be a promising target for hepatocellular carcinoma therapeutics. To obtain invasive ability in early metastasis, EMT is an essential process that epithelial cells use to transform from an epithelial to a mesenchymal phenotype, with remarkable morphologic alterations This is accompanied by decreased expression of epithelial markers (E-cadherin and β-catenin) and increased expression of mesenchymal markers and adhesion proteins (N-cadherin, vimentin, and fibronectin)[19]. Recent studies have revealed that several transcription factors, including Snail, Slug, ZEB1, and SIP, are involved in EMT induction When these transcription factors are overexpressed in cancer cells, they repress E-cadherin, leading to the induction and promotion of EMT26. Pharmacologic inhibition of EMT is considered an important treatment strategy to improve the prognosis for HCC patients

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