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Open Access Research article

Genistein inhibits tumor invasion by suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells

Shulhn-Der Wang5, Bor-Chyuan Chen2, Shung-Te Kao34, Ching-Ju Liu2 and Chia-Chou Yeh12*

Author Affiliations

1 School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan

2 Department of Chinese Medicine, Buddhist Dalin Tzu Chi General Hospital, 2 Min-Sheng Road, Dalin Town, Chia-Yi 62247, Taiwan

3 School of Chinese Medicine, China Medical University, Taichung, Taiwan

4 Division of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan

5 School of Post-Baccalaureate Chinese Medicine, Collage of Chinese Medicine, China Medical University, Taichung, Taiwan

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BMC Complementary and Alternative Medicine 2014, 14:26  doi:10.1186/1472-6882-14-26

Published: 16 January 2014

Abstract

Background

Genistein (Gen) exhibits anti-mutagenic and anti-metastatic activities in hepatoma cell lines. Gen has suppressive effects on tumor growth and angiogenesis in nude mice. Gen suppresses the enzymatic activity of matrix metalloproteinase (MMP)-9; however, the mechanism underlying its anti-invasive activity on hepatocellular carcinoma (HCC) cells is unclear.

Methods

In this study, the possible mechanisms underlying Gen-mediated reduction of 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced cell invasion and inhibition of secreted and cytosolic MMP-9 production in human hepatoma cells (HepG2, Huh-7, and HA22T) and murine embryonic liver cells (BNL CL2) were investigated.

Results

Gen suppressed MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-κ B (NF-κB) activity. Gen suppressed TPA-induced AP-1 activity through inhibitory phosphorylation of extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways, and TPA-stimulated inhibition of NF-κB nuclear translocation through IκB inhibitory signaling pathways. Moreover, Gen suppressed TPA-induced activation of ERK/phosphatidylinositol 3-kinase/Akt upstream of NF-κB and AP-1.

Conclusions

Gen and its inhibition of multiple signal transduction pathways can control the invasiveness and metastatic potential of HCC.

Keywords:
Genistein; TPA; Matrix metalloproteinase 9; Tumor invasion; Nuclear factor-κB; Activator protein 1