Despite significant advances in EOC treatment, including surgery, chemotherapy, radiotherapy, and novel targeted agents, EOC had remained an intractable cancer over the past several decades. Therefore, uncovering the etiological and molecular mechanisms underlying EOC is of vital importance for cancer therapy and prevention. For many years, bioinformatics analysis has been playing crucial roles in cancer study, and it facilitates the understanding of carcinogenesis by integrating data at the genome level with systematic bioinformatics methods. Among the multiple bioinformatics strategies, DNA microarray gene expression profiling has been widely applied to explore DEGs involved in tumorigenesis, diagnosis, and therapeutic approaches .
In this study, we first screened DEGs from three independent GEO datasets, and implemented GO-KEGG pathways enrichment analysis. A PPI network was constructed in the STRING database and the top 20 hub genes were selected in Cytoscape. We then implemented literature retrieval of the 20 genes in Pubmed. Five genes were found having only one or two research papers published previously, including CDC45, CDCA5, KIF4A, ESPL1, and SPAG5. Although there was only one research paper found focusing on the gene SPAG5, the correlation of this gene with the ovarian cancer had been explored deeply in the paper. Therefore, we focused on the other four hub genes in our subsequent research. The relative expression of the four genes, CDC45, CDCA5, KIF4A, and ESPL1, was detected in Oncomine and GEPIA databases, suggesting that all the four hub genes were up-regulated in EOC tissues with statistical significance. Clinical stage analysis indicated that the expression of these four genes decreased gradually with the continuous progression of OC. Survival curves illustrated that patients with a lower level of CDCA5 and ESPL1 had better overall survival and progression-free survival compared to patients with higher expression. Therefore, these two hub genes, CDCA5 and ESPL1, could be utilized as potential diagnostic indicators for EOC.
Cell-division cycle-associated 5 (CDCA5), also known as sororin, is thought to play a critical role in ensuring the accurate separation of sister chromatids during the S and G2/M phases of the cell cycle through interactions with cohesin and cdk1 [10, 11]. CDCA5 has also been shown to interact with ERK as well as cyclin E1, a critical regulator of the G1/Smitotic checkpoint [10–12]. Recent studies have correlated the expression of CDCA5 with tumorigenesis and tissue invasion in several cancers.
Regarding lung cancer, several researches confirmed that CDCA5, exhibiting high specificity and sensitivity to distinguish malignant lesions from non-malignant tissues and associated with poor survival, could be identified as predictive biomarkers for tumorigenesis and poor prognosis of lung adenocarcinomas [13, 14]. In study performed by Nguyen et al, suppression of CDCA5 expression inhibited the growth of lung cancer cells; concordantly, induction of exogenous expression of CDCA5 conferred growth-promoting activity in mammalian cells. Their data suggested that transactivation of CDCA5 and its phosphorylation at Ser209 by ERK played an important role in lung cancer proliferation, and that the selective suppression of the ERK-CDCA5 pathway could be a promising strategy for cancer therapy .
In researches of hepatocellular carcinoma (HCC), CDCA5 was also found to be up-regulated in HCC cells, and related to poor prognosis . CDCA5 participated the promotion of HCC cells proliferation, migration, and invasion, palying a tumor-promotive role and being a potential therapeutic target for patients with HCC [16, 17]. Besides, CDCA5 was found to be transcribed by E2F1, and could promote oncogenesis by enhancing cell proliferation and inhibiting apoptosis via the AKT pathway in HCC . Another research found that increased CDCA5 expression was associated with increased tumor diameter and microvascular invasion in HCC . Furthermore, silencing of CDCA5 inhibited cell proliferation and induced G2/M cycle arrest in vitro, and CDCA5 down-regulation in xenograft model impeded HCC growth in vivo. CDCA5 depletion decreased the levels of ERK 1/2 and AKT phosphorylation in vitro and in vivo. Taken together, theses results indicated that CDCA5 might act as a novel prognostic biomarker and therapeutic target for HCC .
In addition, it has also been confirmed that CDCA5 was significantly upregulated in breast cancer, bladder cancer, oral squamous cell cancer, urinary tract carcinoma, head and neck squamous cell carcinoma, and esophageal squamous cell carcinoma, and the high expression of CDCA5 was closely related to pathological stages and poor prognosis of patients [21–26].
ESPL1, also known as extra spindle poles-like 1 protein or separin, plays a central role in chromosome segregation by cleaving the cohesin complex at the onset of anaphase , and altered ESPL1 activity is correlated with aneuploidy and cancer . At present, the results on the roles of ESPL1 in cancers are conflicting.
ESPL1 expression has been found to be upregulated in a wide range of cancers and high expression of ESPL1 is associated with a loss of key tumor suppressor gene P53, which further contributes to the progression of mammary adenocarcinomas [29, 30]. The research conducted by Finetti et al reinforced that ESPL1 was a candidate oncogene in luminal B breast cancer, and the expression of ESPL1 might represent a promising therapeutic approach for the poor-prognosis tumors . Genomic analysis of transitional cell carcinoma (TCC) by both whole-genome and whole-exome sequencing of 99 individuals with TCC found frequent alterations in ESPL1 . Chen et al found that ESPL1 may be associated with bladder cancer development and recurrence . In addition, Liu et al. identified 7 pivotal genes involved in endometrial cancer prognosis and constructed a prognostic gene signature, among which ESPL1 was one of the genes that were viewed as risky prognostic genes . ESPL1 expression was found to be increased in endometrial cancer tissues, but the clinical significance and functional mechanism of ESPL1 in EC remains to be verified . Nevertheless, it has also been reported that ESPL1 plays an opposite role in gastric adenocarcinoma. ESPL1 expression was negatively correlated with gastric adenocarcinoma pathologic stage progression, and the high expression of ESPL1 was significantly correlated with favorable outcomes . Further work is required to resolve the conflicting roles of ESPL1 in cancer and determine its functions in cancers including the ovarian cancer.
There are several limitations in our study as follows. First, there is an urgent need for biological experiments to validate our results because our research is based on data analysis. Second, we lack the molecular mechanisms for these genes, and we will incorporate these for further exploration. In the future, we will further design experiments (including PCR, Western Blot, immunohistochemistry, etc.) based on specific mechanisms, conduct in-depth research, and improve the inadequacies.