Glioma is the most common and lethal type of brain tumor, which accounts for 46% of intracranial tumors[16]. With the development of sequencing technology, molecular factors for prognosis of glioma have been well studied, such as IDH mutations, 1p/19q co-deletion, ATRX mutation, TERT promoter mutation and PTEN loss[17–20]. Howerer, traditional therapeutic approaches, including surgery, radiotherapy, chemotherapy and targeted therapy do not achieve satisfactory results. Genome differences in patients with glioma make different prognosis of patients. It is necessary for us to explore more prognostic markers to further understand the mechanism of glioma and predict prognosis of patients with glioma. The researches of cancer development revealed that CDCA2 was related to the occurrence and development in multiple cancers[11, 12, 21, 22]. To our knowledge, the expression of CDCA2 and its potential prognostic impact on glioma has not been explored. The potential role of CDCA2 in glioma is the focus in our present study.
In the present study, bioinformatic analysis using high throughout RNA-sequencing data from TCGA and CGGA revealed that an increased expression of CDCA2 in glioma was associated with advanced clinical pathologic characteristics (old age, recurrent status, high grade and GBM sub-type), shorter survival time and poor prognosis. Further, multivariate Cox proportional hazards analysis showed that increased expression of CDCA2 was demonstrated to be an independent prognostic factor in the survival time of patients with glioma in CGGA dataset. To investigate the function of CDCA2 in glioma, we conducted GSEA using CGGA data. GSEA showed that cell regulation pathways were enriched in CDCA2 high expression phenotype. Pearson’s correlation analysis also showed that increased expression of CDCA2 was positively correlated with well-known key cell regulation genes. This suggested that CDCA2 might serve as a potential marker of prognosis and therapeutic target in glioma.
Previous study reported that the expression of CDCA2 mRNA was higher in neuroblastoma than that of lower stage tumor[14]. CDCA2 was also over-expressed in other cancer types and associated with poor prognosis. Recent study demonstrated that CDCA2 promoted colorectal cancer cells proliferation by activating the AKT/CCND1 pathway in vitro and in vivo[11]. More studies were carried out to identify that CDCA could be an signature gene with prognostic value for luminal breast cancer, esophageal squamous cell carcinoma, bladder cancer, melanoma and Synovial sarcoma[12, 13, 21, 23]. In this work, we also demonstrated that strong expression of CDCA2 in glioma was associated with advanced clinical pathologic characteristics and higher expression of CDCA2 was an an independent prognostic indicator associated with poor survival in glioma.
CDCA2 was first identified by Walker as a novel cell-cycle associated gene using mircoarray analyses of co-expression of the well-known cell-cycle genes[10]. Mulcahy and Lamond further revealed that CDCA2 binded to protein phosphatase 1 (PP1), responsible for the targeting of PP1 to chromatin in anaphase. CDCA2/PP1 complex was involved in cell cycle regulation and proliferation[24].Vagnarelli demonstrated that the CDCA2/PP1 complex was critical component of the chromatin reorganization machinery responsible for chromosome de-condensation at the transition from mitosis to G1[25]. Moreover, the study showed that the complex modulated ATM activation, setting the threshold for checkpoint activation[9, 26, 27]. CDCA2 was released from the chromatin at DNA damage sites, which presumably facilitated DNA damage response (DDR) activation[8]. DDR was activated in pre-cancerous cells as a barrier to suppress cell proliferation, cancer progress and reduced in late-stage cancer cells. It was possible that strong expression of CDCA2 could result in desensitization of cells to DDR[28]. Depletion of CDCA2 re-actives the DDR and drive the cells into apoptotic pathway[29]. In our study, we observed that CDCA2 high expression phenotype was associated with cell cycle checkpoint, cell cycle G1/S phase transition, DNA damage checkpoint and regulation of cell cycle arrest in GSEA analysis. In OSCC cell line, depletion of CDCA2 caused a decrease in cell proliferation due to cell cycle arrest in G1 phase and down-regulation of CDK4, CDK6, Cyclin D1/E[22]. In our study, we also demonstrated that the expression of CDCA2 was positively correlated with expressions of well-known key cell cycle regulation genes (CCNA2, CCNB1, CCNB2, CCNE1, CCNE2, CDK1, CDK2, CDK4, CDK6). Cyclin family plays a pivotal part in cell cycle regulation and is involved in a range of biological processes[30, 31]. CDKs, a family of proteins that are involved in the regulation of the cell cycle, are frequently over-expressed or mutated in cancer, and CDK2/4/6 inhibitors (CDK2/4/6i) have been developed to be relatively safe and effective cancer therapeutics[32, 33]. From the work presented above, it appears that the CDCA2 may be a crucial functional factor in mitosis and a crucial hub for the regulation of chromatin organization and the maintenance of genome stability. Further work is needed to determine what is the molecular role of CDCA2 in glioma cell cycle regulation pathway and can it be a potential target therapy for glioma treatment? However, the prediction expression of protein using mRNA expression was far from perfect. The correlation between CDCA2 mRNA expression and CDCA2 protein expression could not be clearly identified because of the limitation in our study. Further study in patients with glioma is required.
In conclusion, high CDCA2 expression may be used as an independent prognostic molecular indicator of poor survival in patients with glioma. Moreover, the expression of CDCA2 was positively correlated with expressions of well-known key cell cycle regulation genes, and the cell cycle regulation pathway may be the key pathway regulated by CDCA2 in glioma. Further experimental validation required to prove the biological impact of CDCA2 in glioma.