Arctigenin Attenuates Tumor Metastasis Through Inhibiting Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma via Suppressing GSK3β-Dependent Wnt/β-Catenin Signaling Pathway In Vivo and In Vitro.

Zheng Lu,Lingling Chang,Yinqian Li,Xiaoqiang Liu,Dewen Tong,Tiejun Mi,Hongbo Zhou

doi:10.3389/fphar.2019.00937

Zheng Lu, Lingling Chang + Show 5 more

Open Access

https://doi.org/10.3389/fphar.2019.00937

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Abstract

Arctigenin (ARG) has been reported to be a bioactive lignan from Arctium lappa exerting various activities including anti-cancer and immune-regulation. The present study aimed to investigate the anti-metastasis activity and mechanism of ARG against hepatocellular carcinoma in vitro and in vivo. The results showed that ARG exhibited a significant cytotoxicity on Hep G2 and SMMC 7721 cells (but not on normal liver cells LO2). In addition, the migration and invasion of Hep G2 and SMMC 7721 cells were also remarkably repressed. Furthermore, ARG attenuated Wnt/β-catenin signaling activation, resulting in the down-regulation of β-catenin target genes including c-Myc, cyclin D1, MMP-9, and ZO-1. Noticeably, ARG attenuated the activation of Wnt/β-catenin through a GSK3β-dependent pathway. Besides, we also found that ARG potentially inhibited epithelial–mesenchymal transition by up-regulating the epithelial and down-regulating the mesenchymal marker proteins. In vivo, intraperitoneal injection of ARG not only significantly inhibited the growth of subcutaneous transplanted tumor but also dramatically alleviated the tumor metastasis in liver. Our data demonstrated that ARG exerted anti-epithelial–mesenchymal transition and anti-metastasis activities against hepatocellular carcinoma, which might make it a candidate as a preventive agent for cancer metastasis.

Highlights

Hepatocellular carcinoma (HCC) is one of the most common human malignancies; majority of the patients usually manifest a poor prognosis (Xie et al, 2019)
Rabbit polyclonal antibodies against p-glycogen synthase kinase 3β (GSK3β), N-cadherin, and E-cadherin; rabbit monoclonal antibodies against c-Myc and cyclin D1; and mouse monoclonal antibodies against vimentin and matrix metalloproteinases (MMP)-9 were purchased from Abcam (Cambridge, UK)
Treatment with ARG obviously suppressed the invasiveness of Hep G2 and SMMC 7721 cells to pass through the matrigel and membrane barriers in the trans-well (Figures 2E, F)

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common human malignancies; majority of the patients usually manifest a poor prognosis (Xie et al, 2019). Early-stage and primary hepatic carcinoma can be treated by surgery, radiofrequency ablation, and transarterial chemoembolization, most cases eventually develop locally advanced or metastatic diseases, which cannot be treated using. Hepatocellular carcinoma is the second most common cause of cancer-related deaths in China and the third leading cause of death in the world (Omata et al, 2017). Accumulating evidences suggested that the high metastatic potential is the pivotal reason that caused the high mortality in malignancies including hepatocellular carcinoma (Mehlen and Puisieux, 2006). The treatment for metastatic cancer is to control the metastasis and improve patient survival, as opposed to curing the disease. More and more attentions have been paid to develop novel anti-cancer agents targeting molecules involved in the development and maintenance of tumor metastasis (Wan et al, 2013; He et al, 2015)

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