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

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.

• Authors: Laura Rubbia-Brandt, Sébastien Tauzin, Catherine Brezault, Céline Delucinge-Vivier, Patrick Descombes, Bertand Dousset, Pietro E Majno, Gilles Mentha, Benoit Terris
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 4 Pg. 687-96 (Apr 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21330458 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCL20 protein, human
• Chemokine CCL20
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Organoplatinum Compounds
• Vascular Endothelial Growth Factor C
• Oxaliplatin

Topics

• 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
• Oxaliplatin
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (genetics)
• Vascular Endothelial Growth Factor C (genetics, metabolism)