The present study represents a focused effort to identify potential OC-related biomarkers that could be useful in effective OC prognosis. We used integrated bioinformatics tools to analyze three microarray datasets (GSE14407, GSE36668 and GSE18520) and processed the data from a total of 73 cancerous (OC) and 26 normal ovarian tissue samples. The analysis with GEO2R revealed a total of 232 common DEGs (p-value < 0.05 and |logFC| > 2), including 108 upregulated (log FC > 0) and 124 downregulated (log FC < 0) genes. Further, GO and pathway enrichment analysis via DAVID showed that for BP, the upregulated genes were involved in cell adhesion, cellular response to interleukin-1, positive regulation of transcription from DNA/RNA, and transcription. Whereas, for CC, these genes were enriched in extracellular matrix/region, anchored membrane component, cell junction and golgi membrane. As for MF, the upregulated genes were mainly enriched in sequence-specific DNA binding, transcription factor activity, RNA polymerase II regulatory region, and DNA binding. The KEGG pathway analysis showed that 26 genes were mainly involved in cell cycle, p53 signaling and oocyte meiosis pathways. Re-analysis of these candidate genes that 13 DEGs were related to significantly higher expression in OC tissues compared to the normal tissues. Of these, 11 genes (CDC6, CCNE1, BUB1B, CCNB2, BUB1, SFN, TTK, CDC20, PTTG1, CDK1 and CDKN2A) were found to be significantly generated and enriched (p < 0.05) in the cell cycle pathway, while 2 genes (SFN and RRM2) were significantly enriched (p < 0.05) in p53 signaling pathway. Our findings reveal new potential candidate genes that could further be targeted for improved ovarian cancer prognosis.
The cell division cycle 6 or CDC6 is a novel initiator of DNA replication and it plays a vital role in the initiation and regulation of the cell cycle [8]. Several studies have reported that CDC6 plays a key role in human cancers including squamous cell carcinoma (SCC) of head and neck, nasopharyngeal carcinoma and lung cancer [9–11]. Remarkably, a significantly higher expression of CDC6 has been associated with epithelial ovarian cancer (EOC) tissues compared to the normal ones [12]. The prognostic significance of this gene in OC and other forms of cancers [13] makes it important target for therapeutic strategies.
Furthermore, our results revealed additional genes like cyclin-dependent kinase 1 (CDK1), cyclin E1 (CCNE1) and cyclin-dependent kinase inhibitor 2A (CDKN2A) that exhibited significantly higher expression in the OC tissues. A recent study by Yunoki and coworkers demonstrated that these three genes were significantly upregulated in the sebaceous gland carcinoma (SGC) of eyelid [14]. Interestingly, CDKN2A is the most widely studied gene for its tumor suppressive activity. Also, any mutation in this gene or disruption in its functional regulation are frequently associated with different types of cancers in human [15, 16].
BUB1 is a serine/threonine kinase that binds centromeres during the process of mitosis. Studies have demonstrated that upregulation of BUB1 is associated with various types of human cancers and subsequently their clinical prognosis [17]. Another study reported that a positively higher percentage of BUB1 protein denotes an advanced stage and higher degree of differentiation in the endometrial carcinoma patients [18]. On the other hand, BUB1B, a mammalian homolog of yeast Mad3, has been shown to elevate the proliferation of tumor and is related to worse survival rates in different forms of cancers including breast, colorectal, prostate and gastric cancer [19–21].
Remarkably, the higher expression of stratafin (SFN) has been designated as a universal abnormality and it is associated with progression of lung adenocarcinoma [22]. In case of human ovarian cancer, the prognostic importance of SFN has been demonstrated earlier. For example, regarding the clinical significance of SFN mRNA, a study has shown that SFN is a cell cycle-related checkpoint gene that is associated with oncogenesis. The higher expression of SFN was observed in different cells of the OC patients and it was reported that higher expression of SFN has association with age and cancer levels [23]. In short, SFN plays a vital role in the regulation of cell cycle and OC pathogenesis [24].
The RRM2 or ribonucleotide reductase subunit M2 is associated with 2p25 chromosome which lacks the structural variations in cervical cancer samples [25]. In addition to being a potential indicator of poor prognosis [26–30], the overexpression of RRM2 has frequently been observed in various forms of cancers including gastric, lung, adrenocortical, nasopharyngeal cancer and neuroblastoma [31–34]. While in our analysis we found that RRM2 is associated with p53 signaling pathway. Given the well-known role of p53 signaling pathways in cancers [35], it could be a potential prognostic biomarker in case of OC.
As several studies have demonstrated that the variable expression of the above-described genes is not only associated with different forms of cancers (including OC), but also, these genes could be a potential candidates for improved OC prognosis. While our study provides the useful information on potential OC biomarkers, in future, these findings should be validated by proper experimentation.