Identification of Genes With Differential Expression in Chemoresistant Epithelial Ovarian Cancer Using High-Density Oligonucleotide Microarrays

Abstract

A major obstacle in treatment of epithelial ovarian cancer is chemoresistance. The aim of this study was to determine whether distinct gene expression profiles are associated with chemoresistance in epithelial ovarian carcinoma. We performed global gene expression analysis in 13 primary epithelial ovarian cancer tissues including 5 primary chemosensitive tumors and 8 primary chemoresistant tumors using Affymetrix HGU133A microarray. The gene expression patterns of chemosensitive tumors were compared with those of chemoresistant tumors using fold change. Validity of microarray results was examined by semiquantitative RT-PCR. We identified over 320 genes differentially expressed in chemoresistant epithelial ovarian cancer (> or = twofold). Upregulated genes in chemoresistant tumors included cell cycle regulating genes (TOP2A, BCAT1, CDCA8, CCNA2, CENPE), and genes with previously known mechanisms in tumorigenesis (S100A9, APOA1, RNF125, IFI16). Downregulated genes in chemoresistant tumors included genes related to cell adhesion (MUC5B, CITED2), transcription regulating genes (FOXD1, MAD1L1, PAX2), genes involving signal transduction (SOSTDC1, SNX1, SFRP1, FOXA2, PLK2), and stress protein gene (TP53AP1). These data show that gene expression profiling can discriminate primary chemoresistant from primary chemosensitive ovarian cancers. This type of molecular profiling could provide a basis for additional functional studies.

Transcriptional Activation of Human CDCA8 Gene Regulated by Transcription Factor NF-Y in Embryonic Stem Cells and Cancer Cells

“…Patients with gastric or lung cancer showing higher nuclear accumulation or expression of CDCA8 represented a shorter tumor-specific survival period (11,12). Compared with chemosensitive tumors, CDCA8 has higher expression in chemoresis- tant epithelial ovarian tumors, suggesting its role in the chemoresistance of cancer (13). In this study, the high levels of CDCA8 transcription in hESCs and early embryonic cells dropped dramatically after differentiation.…”

“…Overexpression of the CPC components Aurora B (4,5), INCENP (6), and survivin (7)(8)(9)(10) is associated with tumorigenesis in human cancers. CDCA8 is a putative oncogene that is up-regulated in many types of cancer tissues (11)(12)(13)(14) but has very low or absent expression in normal tissues (12). Its overexpression is required for growth, survival, and the malignant nature of lung cancer cells (12).…”

Polo-like Kinase Plk2 Is an Epigenetic Determinant of Chemosensitivity and Clinical Outcomes in Ovarian Cancer

“…Our results imply that analysis of Plk2 methylation may have utility as a biomarker of both disease activity and chemosensitivity in EOC. In the context of our results, Plk2 has been identified as a significantly downregulated gene in chemotherapy-resistant primary ovarian carcinomas, affording independent validation of our hypothesis for it being a determinant of chemotherapy sensitivity and candidate biomarker in EOC (32). An important feature of the taxane-resistant cell line models we used in the current study is their cross-resistance with platinum agents.…”

Platinum-Based Chemotherapy Induces Methylation Changes in Blood DNA Associated with Overall Survival in Patients with Ovarian Cancer

“…Further investigation of the candidate genes identified in this study (Supplementary Table S4) may provide novel insight into platinum resistance. Indeed, two have previously been implicated in platinum resistant ovarian cancer including down-regulation of DUSP6 associated with platinum resistance in ovarian cancer cell lines (24) and MAD1L1 down regulation in chemoresistant primary ovarian cancers (25).…”