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Networking of differentially expressed genes in human cancer cells resistant to methotrexate

Elisabet Selga1, Carlota Oleaga, Sara Ramírez

  • 1Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Diagonal Avenue, E-08028 Barcelona, Spain. eliselga@ub.edu.

Genome Medicine
|September 8, 2009
PubMed
Abstract

Insights

Network analysis identified key genes, including DKK1, UGT1A, and EEF1A1, involved in methotrexate (MTX) resistance. Targeting these genes with siRNA chemosensitized cancer cells to MTX, offering potential therapeutic strategies.

Area of Science:

  • Genomics
  • Systems Biology
  • Cancer Research

Background:

  • High-throughput technologies necessitate integrated data analysis through network approaches.
  • Network analyses are crucial for understanding how external factors, like drug treatments, impact gene expression.
  • Biological association networks were constructed to investigate gene expression patterns in methotrexate (MTX)-resistant cancer cell lines.

Purpose of the Study:

  • To construct and analyze biological association networks of genes differentially expressed in MTX-resistant cell lines.
  • To identify key gene nodes associated with MTX resistance across various cancer types.
  • To validate the role of identified genes in MTX resistance using functional experiments.

Main Methods:

  • Utilized seven diverse cancer cell lines representing colon, breast, pancreatic, leukemia, and osteosarcoma.
  • Determined differential gene expression between sensitive and MTX-resistant cells using whole human genome microarrays.
  • Generated biological association networks from commonly deregulated genes using Pathway Architect software.

Main Results:

  • Dikkopf homolog-1 (DKK1) was identified as a key node in colon cancer cell lines; siRNA targeting DKK1 sensitized cells to MTX.
  • UDP-glucuronosyltransferase 1A (UGT1A) family genes formed a network in breast cancer cell lines; siRNA against UGT1A increased MTX sensitivity.
  • Eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) was overexpressed in pancreatic cancer, leukemia, and osteosarcoma cell lines; siRNA targeting EEF1A1 led to MTX chemosensitization.

Conclusions:

  • Biological association networks successfully identified DKK1, UGT1As, and EEF1A1 as critical gene nodes in MTX resistance.
  • siRNA-mediated targeting of DKK1, UGT1As, and EEF1A1 demonstrated chemosensitization to MTX, highlighting their therapeutic potential.

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