The Chinese medicine Sini-San inhibits HBx-induced migration and invasiveness of human hepatocellular carcinoma cells.

Hung-Jen Lin,Shung-Te Kao,Chia-Chou Yeh,Yu–Miao Siao

doi:10.1186/s12906-015-0870-6

Abstract

BackgroundSini-San (SNS) is a formulation of four Traditional Chinese Drugs that exhibits beneficial therapeutic effects in liver injury and hepatitis. However, there are no reports describing its effects on the hepatitis B X-protein (HBx)-induced invasion and metastasis in hepatoma cells, and the detailed molecular mechanisms of its actions are still unclear.MethodsIn this study, we investigated the mechanisms underlying SNS-mediated inhibition of HBx-induced cell invasion and the inhibition of secreted and cytosolic MMP-9 production, using gelatin zymography and Western blot analysis in a human hepatoma cell line (HepG2). Relative luciferase activity was assessed for MMP-9, NF-κB, or AP-1 reporter plasmid-transfected cells.ResultsSNS suppressed MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-κ B (NF-κB) activity. SNS suppressed HBx-induced AP-1 activity through inhibition of phosphorylation in the extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways. SNS also suppressed HBx-induced inhibition of NF-κB nuclear translocation through IκB and suppressed HBx-induced activation of ERK/phosphatidylinositol 3-kinase/Akt upstream of NF-κB and AP-1.ConclusionsSNS suppresses the invasiveness and metastatic potential of hepatocellular carcinoma cells by inhibiting multiple signal transduction pathways.

Highlights

Sini-San (SNS) is a formulation of four Traditional Chinese Drugs that exhibits beneficial therapeutic effects in liver injury and hepatitis
We demonstrated that the inhibition of hepatitis B X-protein (HBx)-induced matrix metalloproteinases (MMPs)-9 activity by SNS in hepatoma cells occurs via nuclear factor-κ B (NF-κB) and activator protein (AP)-1 signaling
HBx expression in HepG2 cells and Cell Viability To determine whether HBx modulates the expression of MMP-9, we first confirmed whether HBx and the HBxGFP fusion protein were expressed in HBx-transfected cells treated with or without DOX

Summary

Introduction

Sini-San (SNS) is a formulation of four Traditional Chinese Drugs that exhibits beneficial therapeutic effects in liver injury and hepatitis. There are no reports describing its effects on the hepatitis B X-protein (HBx)-induced invasion and metastasis in hepatoma cells, and the detailed molecular mechanisms of its actions are still unclear. Sini-San (SNS) comprises four prescriptions of Traditional Chinese Medicine (TCM) used in the treatment of various types of liver disease This formulation was first described in “Treatise on Cold-induced Febrile Diseases (Shanghan Lun),” written by the famous Chinese physician Zhang Zhongjing (150 to 219 A.D. in the Chinese Eastern Han Dynasty). SNS has been used clinically routinely and has produced beneficial effects on liver injury [26, 27], hepatitis [28], chronic stress model [29], and Palmoplantar hidrosis [30] The formulation shows both hepatoprotective activity and a virus clearing effect in patients with hepatitis [28]. We demonstrated that the inhibition of HBx-induced MMP-9 activity by SNS in hepatoma cells occurs via NF-κB and AP-1 signaling

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