Abstract
Tumor recurrence occurs in more than 70% of ovarian cancer patients, and the majority eventually becomes refractory to treatments. Ovarian Cancer Stem Cells (OCSCs) are believed to be responsible for the tumor relapse and drug resistance. Therefore, eliminating ovarian CSCs is important to improve the prognosis of ovarian cancer patients. However, there is a lack of effective drugs to eliminate OCSCs because the core signaling pathways regulating OCSCs remain unclear. Also it is often hard for biologists to identify a few testable targets and infer driver signaling pathways regulating CSCs from a large number of differentially expression genes in an unbiased manner. In this study, we propose a straightforward and integrative analysis to identify potential core signaling pathways of OCSCs by integrating transcriptome data of OCSCs isolated based on two distinctive markers, ALDH and side population, with regulatory network (Transcription Factor (TF) and Target Interactome) and signaling pathways. We first identify the common activated TFs in two OCSC populations integrating the gene expression and TF-target Interactome; and then uncover up-stream signaling cascades regulating the activated TFs. In specific, 22 activated TFs are identified. Through literature search validation, 15 of them have been reported in association with cancer stem cells. Additionally, 10 TFs are found in the KEGG signaling pathways, and their up-stream signaling cascades are extracted, which also provide potential treatment targets. Moreover, 40 FDA approved drugs are identified to target on the up-stream signaling cascades, and 15 of them have been reported in literatures in cancer stem cell treatment. In conclusion, the proposed approach can uncover the activated up-stream signaling, activated TFs and up-regulated target genes that constitute the potential core signaling pathways of ovarian CSC. Also drugs and drug combinations targeting on the core signaling pathways might be able to eliminate OCSCs. The proposed approach can also be applied for identifying potential activated signaling pathways of other types of cancers.
Highlights
Over 90% of ovarian cancers are epithelial in origin, and epithelial ovarian cancer, especially the most aggressive subtype high-grade serous ovarian cancer (HGSOC), accounts for the majority of ovarian cancer deaths [1, 2]
With the aim of discovering testable regulatory signaling networks that maintain Ovarian cancer stem cells (CSCs), we identify the activated transcription factors (TFs) in both datasets (CSCs isolated from ALDH+ marker and side-population) using the Fisher’s exact test by integrating the up-regulated genes (Fold_Change > = 2) and the TF-target interactome data
We identified 22 activated transcription factors, and 15 of them have been reported in the association with cancer stem cells
Summary
Over 90% of ovarian cancers are epithelial in origin, and epithelial ovarian cancer, especially the most aggressive subtype high-grade serous ovarian cancer (HGSOC), accounts for the majority of ovarian cancer deaths [1, 2]. Drugs targeting on the upstream signaling cascades of activated TFs are selected as potential treatments to eliminate ovarian cancer stem cells.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have