Ovarian cancer stem cell-specific gene expression profiling and targeted drug prescreening

Abstract

Cancer stem cells, with unlimited self-renewal potential and other stem cell characteristics, occur in several types of cancer, including ovarian cancer (OvC). Although CSCs can cause tumor initiation, malignant proliferation, relapse and multi-drug resistance, ways to eliminate them remain unknown. In the present study, we compared ovarian cancer stem cell (OVCSC) expression profiles in normal ovarian surface epithelium and ovarian cells from patients with advanced disease to identify key pathways and specific molecular signatures involved in OVC progression and to prescreen candidate small-molecule compounds with anti-OVCSC activity. Comparison of genome-wide expression profiles of OvC stemness groups with non-stemness controls revealed 6495, 1347 and 509 differentially expressed genes in SDC, SP1 and SP2 groups, respectively, with a cut-off of fold-change set at >1.5 and P<0.05. NAB1 and NPIPL1 were commonly upregulated whereas PROS1, GREB1, KLF9 and MTUS1 were commonly downregulated in all 3 groups. Most differentially expressed genes consistently clustered with molecular functions such as protein receptor binding, kinase activity and chemo-repellent activity. These genes regulate cellular components such as centrosome, plasma membrane receptors, and basal lamina, and may participate in biological processes such as cell cycle regulation, chemoresistance and stemness induction. Key Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways such as ECM receptor, ErbB signaling, endocytosis and adherens junction pathways were enriched. Gene co-expression extrapolation screening by the Connectivity Map revealed several small-molecule compounds (such as SC-560, disulfiram, thapsigargin, esculetin and cinchonine) with potential anti-OVCSC properties targeting OVCSC signature genes. We identified several key CSC features and specific regulation networks in OVCSCs and predicted several small molecules with potential anti-OVCSC pharmacological properties, which may aid the development of OVCSC-specific drugs.