Knockdown of PPAR δ gene promotes the growth of colon cancer and reduces the sensitivity to bevacizumab in nude mice model

PLoS One. 2013 Apr 8;8(4):e60715. doi: 10.1371/journal.pone.0060715. Print 2013.

Abstract

The role of peroxisome proliferator--activated receptor- δ (PPAR δ) gene in colon carcinogenesis remains highly controversial. Here, we established nude mice xenograft model using a human colon cancer cell line KM12C either with PPAR δ silenced or normal. The xenografts in PPAR δ-silenced group grew significantly larger and heavier with less differentiation, promoted cell proliferation, increased expression of vascular endothelial growth factor (VEGF) and similar apoptosis index compared with those of PPAR δ-normal group. After treated with the specific VEGF inhibitor bevacizumab, the capacities of growth and proliferation of xenografts were decreased in both groups while still significantly higher in PPAR δ-silenced group than in PPAR δ-normal group. Administration of PPAR δ agonist significantly decreased VEGF expression in PPAR δ-normal KM12C cells but not in PPAR δ-silenced cells. These findings demonstrate that, knockdown of PPAR δ promotes the growth of colon cancer by inducing less differentiation, accelerating the proliferation and VEGF expression of tumor cells in vivo, and reduces tumor sensitivity to bevacizumab. This study indicates that PPAR δ attenuates colon carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Bevacizumab
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Knockdown Techniques*
  • Humans
  • Mice
  • Mice, Nude
  • PPAR gamma / deficiency*
  • PPAR gamma / genetics*
  • PPAR gamma / metabolism
  • Vascular Endothelial Growth Factor A / genetics

Substances

  • Antibodies, Monoclonal, Humanized
  • PPAR gamma
  • Vascular Endothelial Growth Factor A
  • Bevacizumab

Grant support

The authors acknowledge grant support from the Natural Science Foundation of China (No. 30801332; http://www.nsfc.gov.cn/), Ph.D. Programs Foundation of Ministry of Education of China (No. 200806100058; http://www.chinapostdoctor.org.cn/), and the Swedish Cancer Foundation (http://www.cancerfonden.se/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.