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Genome Medicine

, 1:83

First Online: 04 September 2009Received: 22 May 2009Revised: 31 July 2009Accepted: 04 September 2009


BackgroundThe need for an integrated view of data obtained from high-throughput technologies gave rise to network analyses. These are especially useful to rationalize how external perturbations propagate through the expression of genes. To address this issue in the case of drug resistance, we constructed biological association networks of genes differentially expressed in cell lines resistant to methotrexate MTX.

MethodsSeven cell lines representative of different types of cancer, including colon cancer HT29 and Caco2, breast cancer MCF-7 and MDA-MB-468, pancreatic cancer MIA PaCa-2, erythroblastic leukemia K562 and osteosarcoma Saos-2, were used. The differential expression pattern between sensitive and MTX-resistant cells was determined by whole human genome microarrays and analyzed with the GeneSpring GX software package. Genes deregulated in common between the different cancer cell lines served to generate biological association networks using the Pathway Architect software.

ResultsDikkopf homolog-1 DKK1 is a highly interconnected node in the network generated with genes in common between the two colon cancer cell lines, and functional validations of this target using small interfering RNAs siRNAs showed a chemosensitization toward MTX. Members of the UDP-glucuronosyltransferase 1A UGT1A family formed a network of genes differentially expressed in the two breast cancer cell lines. siRNA treatment against UGT1A also showed an increase in MTX sensitivity. Eukaryotic translation elongation factor 1 alpha 1 EEF1A1 was overexpressed among the pancreatic cancer, leukemia and osteosarcoma cell lines, and siRNA treatment against EEF1A1 produced a chemosensitization toward MTX.

ConclusionsBiological association networks identified DKK1, UGT1A s and EEF1A1 as important gene nodes in MTX-resistance. Treatments using siRNA technology against these three genes showed chemosensitization toward MTX.

AbbreviationsAPRTAdenine Phosphoribosyltransferase

BANbiological association network

DHFRdihydrofolate reductase

DKK1Dikkopf homolog 1

EEF1A1eukaryotic translation elongation factor 1 alpha 1

MTT3-4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide


NLPNatural Language Processing

SEstandard error

siRNAsmall interfering RNA

TCFT-cell factor

UGTUDP glucuronosyl transferase.

Electronic supplementary materialThe online version of this article doi:10.1186-gm83 contains supplementary material, which is available to authorized users.

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Autor: Elisabet Selga - Carlota Oleaga - Sara Ramírez - M Cristina de Almagro - Véronique Noé - Carlos J Ciudad


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