Meta-analysis of microarray data to determine gene indicators involved in the cisplatin resistance in ovarian cancer.

Abstract

Significant miss-expressed gene indicators contributing to cisplatin resistance in ovarian cancer have not been completely understood. It seems that several regulatory genes and signaling pathways are associated with the emergence of the chemo-resistant phenotype. Here, a meta-analysis approach was adopted to assess deregulated genes involved in relapse after the first line of chemotherapy (cisplatin). To do so, six ovarian cancer libraries were gathered from GEO repository. Batch effect removal and quality assessment, and boxplots and PCA were performed using SVA and ggplot2 packages in R, respectively. Cisplatin-resistant and -sensitive ovarian cancer groups were compared with find genes with significant expression changes using linear regression models in the LIMMA R package. The significance threshold for DEGs was taken as adj p-value < .05 and - 1 > logFC > 1. A total of 261 genes were identified to have significant differential expression levels in the cisplatin-resistant versus cisplatin-sensitive group. Among the 10 top up-regulated and down-regulated genes, PITX2, SNCA, and EPHA7 (up), as well as TMEM98 (down) are indirect upstream regulators of PI3K/AKT signaling pathway, contributing greatly to the development of chemo-resistance in cancer via promoting cell proliferation, survival, and cell cycle progression as well as inhibiting apoptosis. Moreover, a comprehensive assessment of DEGs revealed the dysregulation of not only membrane ion channels KCa1.1, Kv4, and CACNB4, affecting cell excitability, proliferation, and apoptosis but also cell adhesion proteins COL4A6, EPHA3, and CD9, affecting the attachment of normal cells to ECM and apoptosis, introducing good options to reverse cisplatin resistance. Our results predict and suggest that upstream regulators of PI3K/AKT signaling pathway, ion channels, and cell adhesion proteins play important roles in cisplatin resistance development in ovarian cancer.