PPAR(gamma)/PGC-1(alpha) pathway in E-cadherin expression and motility of HepG2 cells

Anticancer Res. 2009 Dec;29(12):5057-63.

Abstract

Background: Peroxisome proliferator-activated receptor gamma (PPARgamma) activation has been proposed as a potential therapeutic strategy for various types of human cancer. The aim of this study was to activate PPARgamma and overexpress PGC-1alpha in HepG2 cells in order to analyze their effects on cell motility and E-cadherin expression.

Materials and methods: Adenovirus-mediated gene transfer was performed to overexpress PGC-1alpha in HepG2 human hepatoma cells. Small interference RNA (siRNA) was used to silence the expression of E-cadherin and PPARgamma. Cell motility was assessed by transwell cell migration analysis. Measurements of mRNA and protein expression were done by quantitative RT-PCR and Western blotting.

Results: Treatment with synthetic PPARgamma agonists, thiazolidinediones (rosiglitazone; troglitazone), and adenovirus-delivered overexpression of PPARgamma transcriptional coactivator-1alpha (PGC-1alpha) up-regulated E-cadherin expression and reduced motility of HepG2 cells. Using PPARgamma antagonist GW9662, we demonstrated that both PPARgamma-dependent and -independent pathways were involved in PGC-1alpha-induced up-regulation of E-cadherin. In addition, siRNA-mediated knockdown of E-cadherin expression restored the motility of PGC-1alpha-overexpressing HepG2 cells, indicating that up-regulated E-cadherin is responsible for the lower migratory ability of these cells. Intriguingly, siRNA-mediated silencing of PPARgamma abolished E-cadherin protein expression but also reduced the motility of HepG2 cells.

Conclusion: PPARgamma/PGC-1alpha pathway plays a crucial role in modulating E-cadherin expression and motility of HepG2 cells and may be a potential target for the prevention of HCC metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cadherins / antagonists & inhibitors
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cell Movement*
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Hep G2 Cells
  • Humans
  • PPAR gamma / antagonists & inhibitors
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Thiazolidinediones / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Cadherins
  • Heat-Shock Proteins
  • PPAR gamma
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • RNA, Messenger
  • Thiazolidinediones
  • Transcription Factors