Abstract
Baicalein, a widely used Chinese herbal medicine, has historically been used in anti-inflammatory and anti-cancer therapies. However, the anti-metastatic effect and molecular mechanism(s) of baicalein on hepatocellular carcinoma (HCC) remain poorly understood. Therefore, the purpose of this study was to assess the anti-metastatic effects of baicalein and related mechanism(s) on HCC. Based on assays utilized in both HCC cell lines and in an animal model, we found that baicalein inhibited tumor cell metastasis in vivo and in vitro. Furthermore, after treatment with baicalein for 24 hours, there was a decrease in the levels of matrix metalloproteinase-2 (MMP-2), MMP-9 and urokinase-type plasminogen activator (u-PA) expression as well as proteinase activity in hepatocellular carcinoma MHCC97H cells. Meanwhile, the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 were increased in a dose-dependent fashion. Moreover, baicalein treatment dramatically decreased the levels of the phosphorylated forms of MEK1 and ERK1/2. MEK1 overexpression partially blocked the anti-metastatic effects of baicalein. Combined treatment with an ERK inhibitor (U0126) and baicalein resulted in a synergistic reduction in MMP-2, MMP-9 and u-PA expression and an increase in TIMP-1 and TIMP-2 expression; the invasive capabilities of MHCC97H cells were also inhibited. In conclusion, baicalein inhibits tumor cell invasion and metastasis by reducing cell motility and migration via the suppression of the ERK pathway, suggesting that baicalein is a potential therapeutic agent for HCC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Antioxidants / administration & dosage
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Antioxidants / chemistry
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Antioxidants / pharmacology
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Carcinoma, Hepatocellular / drug therapy
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism*
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Carcinoma, Hepatocellular / pathology*
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Enzyme Activation / drug effects
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Flavanones / administration & dosage
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Flavanones / chemistry
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Flavanones / pharmacology*
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Liver Neoplasms / drug therapy
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism*
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Liver Neoplasms / pathology*
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MAP Kinase Signaling System / drug effects*
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Male
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Matrix Metalloproteinase 2 / genetics
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Matrix Metalloproteinase 2 / metabolism
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism
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Mice
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Neoplasm Invasiveness
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Neoplasm Metastasis
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Tissue Inhibitor of Metalloproteinase-1 / genetics
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Tissue Inhibitor of Metalloproteinase-1 / metabolism
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Tissue Inhibitor of Metalloproteinase-2 / genetics
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Tissue Inhibitor of Metalloproteinase-2 / metabolism
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Transcription, Genetic
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Urokinase-Type Plasminogen Activator / genetics
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Urokinase-Type Plasminogen Activator / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Antioxidants
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Flavanones
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Tissue Inhibitor of Metalloproteinase-1
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Tissue Inhibitor of Metalloproteinase-2
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baicalein
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Urokinase-Type Plasminogen Activator
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 9
Grants and funding
This research was supported by Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT: 1171), the Fundamental Research Funds for the Central Universities (XJJ2008020). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.