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Gene expression profiling provides insights into pathways of oxaliplatin-related sinusoidal obstruction syndrome in humans

Contributors

Rubbia-Brandt, Laura; Tauzin, Sébastien; Brezault, Catherine; Delucinge-Vivier, Céline; Descombes, Patrick; Dousset, Bertand; Majno, Pietro; Mentha, Gilles; Terris, Benoit

Published in

Molecular cancer therapeutics, vol. 10, no. 4, p. 687-696

Publication date

2011

Abstract

Sinusoidal obstruction syndrome (SOS; formerly veno-occlusive disease) is a well-established complication of hematopoietic stem cell transplantation, pyrrolizidine alkaloid intoxication, and widely used chemotherapeutic agents such as oxaliplatin. It is associated with substantial morbidity and mortality. Pathogenesis of SOS in humans is poorly understood. To explore its molecular mechanisms, we used Affymetrix U133 Plus 2.0 microarrays to investigate the gene expression profile of 11 human livers with oxaliplatin-related SOS and compared it to 12 matched controls. Hierarchical clustering analysis showed that profiles from SOS and controls formed distinct clusters. To identify functional networks and gene ontologies, data were analyzed by the Ingenuity Pathway Analysis Tool. A total of 913 genes were differentially expressed in SOS: 613 being upregulated and 300 downregulated. Reverse transcriptase-PCR results showed excellent concordance with microarray data. Pathway analysis showed major gene upregulation in six pathways in SOS compared with controls: acute phase response (notably interleukin 6), coagulation system (Serpine1, THBD, and VWF), hepatic fibrosis/hepatic stellate cell activation (COL3a1, COL3a2, PDGF-A, TIMP1, and MMP2), and oxidative stress. Angiogenic factors (VEGF-C) and hypoxic factors (HIF1A) were upregulated. The most significant increase was seen in CCL20 mRNA. In conclusion, oxaliplatin-related SOS can be readily distinguished according to morphologic characteristics but also by a molecular signature. Global gene analysis provides new insights into mechanisms underlying chemotherapy-related hepatotoxicity in humans and potential targets relating to its diagnosis, prevention, and treatment. Activation of VEGF and coagulation (vWF) pathways could partially explain at a molecular level the clinical observations that bevacizumab and aspirin have a preventive effect in SOS.

Keywords

  • Chemokine CCL20/genetics/metabolism
  • Cluster Analysis
  • Gene Expression Profiling
  • Hepatic Veno-Occlusive Disease/chemically induced/genetics
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism
  • Immunohistochemistry
  • Liver/metabolism/pathology
  • Microarray Analysis
  • Organoplatinum Compounds
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction/genetics
  • Vascular Endothelial Growth Factor C/genetics/metabolism

UNIGE affiliation entities

UNIGE research groups

Citation (ISO format)

RUBBIA-BRANDT, Laura et al. Gene expression profiling provides insights into pathways of oxaliplatin-related sinusoidal obstruction syndrome in humans. In: Molecular cancer therapeutics, 2011, vol. 10, n° 4, p. 687–696. doi: 10.1158/1535-7163.MCT-10-1072

Main files (1)

Article (Published version)

Identifiers

Journal ISSN

1535-7163
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548downloads

Technical informations

Creation

22/11/2012 14:45:00

First validation

22/11/2012 14:45:00

Update

14/03/2023 17:49:01

Status update

14/03/2023 17:49:01

Last indexation

30/10/2024 08:11:15
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