Increased expression of DNA repair genes in invasive human pancreatic cancer cells

Pancreas. 2011 Jul;40(5):730-9. doi: 10.1097/MPA.0b013e31821ae25b.

Abstract

Objective: Pancreatic cancer was the fourth leading cause of cancer death in the United States in 2010. Recurrence of disease after resection occurs because of neoplastic cell survival. To better understand these highly aggressive cells, gene expression microarrays were performed.

Methods: Using the established lines HPAC and PANC1 and a Matrigel assay, genome expression arrays were performed to analyze patterns between invasive and total cells.

Results: Significant increases in the expression of genes related to DNA repair were observed. A number of the same genes also demonstrated an increase in expression when comparing bulk cells to a putative tumor-initiating cell (TIC) population. The TIC population was isolated using the spheroid technique, and compared with bulk cells, spheroid cells functionally repair breaks in DNA faster after challenge with the drug gemcitabine. Finally, using Oncomine, we observed a significant increase in DNA copy number of BRCA1 and RAD51 in tissue isolated from metastatic pancreatic cancer compared with tissue isolated from the primary site.

Conclusions: From these data, we conclude that the most invasive cells within a pancreatic tumor are able to thrive because of their increased genomic stability. These cells have also been linked to the TIC population in a tumor.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • DNA Repair / genetics*
  • DNA, Neoplasm / genetics
  • DNA, Neoplasm / metabolism
  • Databases, Factual
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Gene Dosage
  • Gene Expression
  • Genes, BRCA1
  • Genomic Instability
  • Humans
  • Neoplasm Invasiveness / genetics
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Rad51 Recombinase / genetics
  • Spheroids, Cellular / drug effects
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology

Substances

  • Antineoplastic Agents
  • DNA, Neoplasm
  • Deoxycytidine
  • gemcitabine
  • RAD51 protein, human
  • Rad51 Recombinase