The antimetastatic effects of resveratrol on hepatocellular carcinoma through the downregulation of a metastasis-associated protease by SP-1 modulation

PLoS One. 2013;8(2):e56661. doi: 10.1371/journal.pone.0056661. Epub 2013 Feb 20.


Background: The mortality and morbidity rates from cancer metastasis have not declined in Taiwan, especially because of hepatocellular carcinoma (HCC). Resveratrol has been shown to have benefits such as cardioprotection, providing antioxidative, anti-inflammatory, anti-cancer properties in previous studies. Therefore, HCC cells were subjected to treatment with resveratrol and then analyzed to determine the effects of resveratrol on the migration and invasion.

Methodology and principal findings: Modified Boyden chamber assays revealed that resveratrol treatment significantly inhibited cell migration and invasion capacities of Huh7 cell lines that have low cytotoxicity in vitro, even at a high concentration of 100 µM. The results of casein zymography and western blotting revealed that the activities and protein levels of the urokinase-type plasminogen activator (u-PA) were inhibited by resveratrol. Western blot analysis also showed that resveratrol inhibits phosphorylation of JNK1/2. Tests of the mRNA level, real-time PCR, and promoter assays evaluated the inhibitory effects of resveratrol on u-PA expression in HCC cells. The chromatin immunoprecipitation (ChIP) assay showed that reactive in transcription protein of nuclear factor SP-1 was inhibited by resveratrol.

Conclusions: Resveratrol inhibits u-PA expression and the metastasis of HCC cells and is a powerful chemopreventive agent. The inhibitory effects were associated with the downregulation of the transcription factors of SP-1 signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticarcinogenic Agents / administration & dosage
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Down-Regulation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Neoplasm Invasiveness / pathology
  • Phosphorylation / drug effects
  • Resveratrol
  • Signal Transduction / drug effects
  • Sp1 Transcription Factor / genetics*
  • Sp1 Transcription Factor / metabolism
  • Stilbenes / administration & dosage*
  • Urokinase-Type Plasminogen Activator / metabolism


  • Anticarcinogenic Agents
  • Sp1 Transcription Factor
  • Stilbenes
  • Urokinase-Type Plasminogen Activator
  • Resveratrol

Grant support

This study was supported by a research grant from Chung Shan Medical University Hospital, Taiwan (CSH-2012-C-006). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.