Abstract
BackgroundCancer stem cells (CSCs) can self-renew, proliferate into differentiated cells, or enter a quiescent state and are regarded to cause chemoresistance and recurrence. An integrative analysis of transcription factors (TF) and miRNAs was performed in ovarian CSC-enriched spheroid-forming cells (SFCs) to identify factors relevant to ovarian CSCs.MethodsFresh tumor cells from three ovarian cancer patients were cultured in standard and in selective medium. The mRNAs and miRNAs that exhibited significant differential expression between SFCs and adherent cells were identified using mRNA and miRNAs microarrays. Target genes of miRNAs were further selected if predicted with TargetScan by half of the miRNAs or more. Gene enrichment analysis was performed on over- or under-expressed mRNAs and target genes of miRNAs using DAVID tools. Complex regulatory networks were combined from TF-genes and miRNA-genes interactions using the MAGIA webtool.ResultsA total of 1245 mRNA and 55 miRNAs were differentially expressed (p-value< 0.05, paired t-test). Elevation of transcription-related processes and suppression of focal adhesion pathway were noted in SFCs, according to the enrichment analyses. Transcriptional hyperactivity is a known characteristic of the stem cell transcriptome. The integrative network suggested that cell cycle was arrested in SFCs where over-expressed EGR1 and under-expressed MYC and miR-130a-3p had multiple connections with target genes.ConclusionsMYC, EGR1, and miR-130a-3p were hubs in our integrative analysis of ovarian CSC-enriched SFCs, suggesting that ovarian cancer SFCs display a stem cell identity with the quiescent phenotype where adhesion- and cell cycle-related genes were suppressed.
Highlights
Cancer stem cells (CSCs) can self-renew, proliferate into differentiated cells, or enter a quiescent state and are regarded to cause chemoresistance and recurrence
In this study we examined and integrated the Messenger RNA (mRNA) expression of transcription factors and miRNA expressions of spheroids derived from primary ovarian cancers to identify factors regulating ovarian cancer stem cells
A total of five patients were initially enrolled, three corresponding sets from 3 patients were studied for matched analysis of mRNA and miRNA expression because one patient was proved to be low grade serous carcinoma, and one sample did not pass the RNA QC for microarray
Summary
Cancer stem cells (CSCs) can self-renew, proliferate into differentiated cells, or enter a quiescent state and are regarded to cause chemoresistance and recurrence. About 70% of cases have intraperitoneal dissemination at initial diagnosis [1]. These cases usually regress completely following primary cytoreductive surgery and adjuvant. Spheroids are proposed to mainly consist of cancer stem cells (CSCs) which have potential to evade therapy [4]. Spheroids in this non-adherent condition enter a quiescent or dormant state, a temporary arrest of proliferation, and become refractory to chemotherapy [5]
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