Role of H2O2 in RET/PTC1 Chromosomal Rearrangement Produced by Ionizing Radiation in Human Thyroid Cells

Cancer Res. 2010 May 15;70(10):4123-32. doi: 10.1158/0008-5472.CAN-09-4336. Epub 2010 Apr 27.

Abstract

During childhood, the thyroid gland is one of the most sensitive organs to the carcinogenetic effects of ionizing radiation that may lead to papillary thyroid carcinoma (PTC) associated with RET/PTC oncogene rearrangement. Exposure to ionizing radiation induces a transient "oxidative burst" through radiolysis of water, which can cause DNA damage and mediates part of the radiation effects. H(2)O(2) is a potent DNA-damaging agent that induces DNA double-strand breaks, and consequently, chromosomal aberrations. Irradiation by 5 Gy X-ray increased extracellular H(2)O(2). Therefore, we investigated the implication of H(2)O(2) in the generation of RET/PTC1 rearrangement after X-ray exposure. We developed a highly specific and sensitive nested reverse transcription-PCR method. By using the human thyroid cell line HTori-3, previously found to produce RET/PTC1 after gamma-irradiation, we showed that H(2)O(2), generated during a 5 Gy X-ray irradiation, causes DNA double-strand breaks and contributes to RET/PTC1 formation. Pretreatment of cells with catalase, a scavenger of H(2)O(2), significantly decreased RET/PTC1 rearrangement formation. Finally, RET/PTC chromosomal rearrangement was detected in HTori-3.1 cells after exposure of cells to H(2)O(2) (25 micromol/L), at a dose that did not affect the cell viability. This study shows for the first time that H(2)O(2) is able to cause RET/PTC1 rearrangement in thyroid cells and consequently highlights that oxidative stress could be responsible for the occurrence of RET/PTC1 rearrangement found in thyroid lesions even in the absence of radiation exposure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Carcinoma, Papillary / genetics
  • Carcinoma, Papillary / metabolism
  • Carcinoma, Papillary / pathology*
  • Cell Differentiation / drug effects
  • Cell Differentiation / radiation effects
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Cells, Cultured
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / drug effects
  • Embryo, Mammalian / radiation effects
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / radiation effects
  • Gene Rearrangement / drug effects
  • Gene Rearrangement / radiation effects*
  • Humans
  • Hydrogen Peroxide / pharmacology*
  • Lung / cytology
  • Lung / drug effects
  • Lung / radiation effects
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Oxidants / pharmacology
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / metabolism
  • Reactive Oxygen Species / metabolism
  • Thyroid Gland / drug effects
  • Thyroid Gland / metabolism
  • Thyroid Gland / radiation effects*
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / pathology
  • X-Rays

Substances

  • Oncogene Proteins, Fusion
  • Oxidants
  • Reactive Oxygen Species
  • Hydrogen Peroxide
  • Protein-Tyrosine Kinases
  • ret-PTC fusion oncoproteins, human