Gene expression analysis of multiple gastrointestinal regions reveals activation of common cell regulatory pathways following cytotoxic chemotherapy

Abstract

Gastrointestinal mucositis involves many changes at the gene level, affecting epithelial/subepithelial interactions and leading to overt damage. The regional specificity and time course of these changes, and how they relate to subsequent mucositis development however remain unknown. The aim of this study was to determine the early time course of gene expression changes along the gastrointestinal tract of the DA rat following chemotherapy. Female DA rats were treated with a single dose of 200 mg/kg irinotecan to induce mucositis, and were killed at short intervals following treatment. Small sections of stomach, jejunum and colon were harvested for analysis of genetic profiles. RNA was hybridised to high density Affymetrix oligonucleotide microarrays. Data analysis was carried out with software package, TimeCourse, freely available through Bioconductor. As early as 1 hr following chemotherapy, expression of hundreds of genes was altered, including those for transcription factors, stress response proteins and protein turnover. These genes are involved in cell proliferation, differentiation and apoptosis along with other cellular processes. At early time points, there was a significant response involving the mitogen-activated protein kinase pathway, cell cycle regulation and cytokine receptor signalling. At later time points, changes to the complement cascade became prominent. We have shown that changes in gene expression following chemotherapy occur by 1 hr, and persist for at least 72 hr after treatment. Many of these changes are highly likely to be specifically related to the subsequent development of gastrointestinal mucositis.