Increased CDCA2 Level Was Related to Poor Prognosis in Hepatocellular Carcinoma and Associated With Up-Regulation of Immune Checkpoints

Abstract

BackgroundCell division cycle-associated protein 2 (CDCA2) is a member of cell cycle-related proteins. CDCA2 plays a role in the regulation of protein phosphatase 1(PP1) γ-dependent DNA damage response (DDR) and H3 phosphorylation. CDCA2 promotes the tumorigenesis and development of several types of cancers by promoting the proliferation of tumor cells. However, the relationship between CDCA2 expression and the clinicopathological characteristics of hepatocellular carcinoma (HCC) is unknown.MethodsGene expression information and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. The expression of CDCA2 and its correlation to clinical characteristics in HCC were analyzed. The expression level of CDCA2 was validated in HCC cell lines. The relationship between CDCA2 expression and the survival of patients with HCC was analyzed by using Kaplan–Meier method. The prognostic value of CDCA2 in HCC was estimated by Cox regression analysis. The expression difference of CDCA2 between HCC and normal tissues and its correlation to survival were verified in independent datasets. Gene set enrichment analysis (GSEA) was used to screen the CDCA2-related signaling pathways.ResultsCell division cycle-associated protein 2 expression was upregulated in HCC tissues (p < 0.001) and increased CDCA2 was correlated to increased T stage, pathologic stage, histologic grade, and alpha-fetoprotein (AFP) level (p < 0.001). In addition, CDCA2 was overexpressed in HCC cell lines HepG2 and LM3. High CDCA2 expression level was associated with poor overall survival [hazard ratio (HR) = 1.69; 95% CI, 1.20–1.40, p = 0.003], disease specific survival (HR = 1.73; 95% CI, 1.11–2.71, p = 0.016), and progress free interval (HR = 1.74; 95% CI, 1.30–2.34, p < 0.001). Overexpression of CDCA2 and its correlation to poor survival in HCC were verified in Gene Expression Omnibus (GEO) datasets and Kaplan–Meier plotter database. Increased CDCA2 expression was associated with upregulation of PD-L1 (Spearman's coefficient = 0.207, p < 0.001), PD-L2 (Spearman coefficient's = 0.118, p < 0.05), and CTLA4 (Spearman's coefficient = 0.355, p < 0.001). GSEA showed that homologous recombination pathway, insulin signaling pathway, mitogen-activated protein kinase (MAPK) pathway, mismatch repair pathway, mechanistic target of rapamycin (mTOR) pathway, Notch pathway, T cell receptor pathway, toll like receptor pathway, and WNT pathway were enriched in CDCA2 high expression phenotype.ConclusionCell division cycle-associated protein 2 may serve as an independent biomarker for poor prognosis in HCC and increased CDCA2 expression was associated with upregulation of immune checkpoints.

Identification of a novel circRNA–miRNA–mRNA regulatory axis in hepatocellular carcinoma based on bioinformatics analysis

“…The potential use of this aptamer in HCC immunotherapy was previously explored 38 . It was also found that the upregulation of immune checkpoint CD274 could increase the expression of cell division cycle-associated protein 2 (CDCA2) and predict the poor prognosis of HCC 39 . We found that ACTG1, E2F3, RASSF3, and WDR76 in the ceRNA network are closely related to the immune checkpoints, suggesting that the ceRNA network regulates the immune escape of HCC cells.…”

CDCA2 Promotes HCC Cells Development via AKT–mTOR Pathway

“…In addition to reports, which revealed that overexpression of CDCA2 is a common event in lung, prostate, and oral cancers, Tang et al reported that CDCA2 was increased in HCC as well based on analyses of data from TCGA [ 17 ]. Furthermore, they suggested that CDCA2 had a high diagnostic power and was associated with poor survival for HCC [ 17 ]. On the basis of these reports, we investigated the effects of CDCA2 on the malignant behaviors of HCC cells using biological experiments in the present study.…”

“…For example, activation of AKT–mTOR pathway contributes to the progression of lung cancer, breast cancer, endometrial cancer, and HCC [ 27 – 30 ]. Using gene set enrichment analysis, Tang et al demonstrated that CDCA2 may be involved in mTOR pathway [ 17 ]. Consistently, by biological experiments, we discovered that overexpression of CDCA2 triggered the increasing of phosphorylation of mTOR and AKT in the present study.…”

“…Besides, CDCA2 high expression may be closely related to oral squamous cell carcinoma, a types of head and neck squamous cell carcinoma (OSCC) development by blocking cell cycle arrest and apoptosis [16]. In addition to reports, which revealed that overexpression of CDCA2 is a common event in lung, prostate, and oral 5 Analytical Cellular Pathology cancers, Tang et al reported that CDCA2 was increased in HCC as well based on analyses of data from TCGA [17]. Furthermore, they suggested that CDCA2 had a high diagnostic power and was associated with poor survival for HCC [17].…”

“…In 2022, Tang et al investigated the expression pattern and the prognostic value of CDCA2 in HCC based on the data from The Cancer Genome Atlas database (TCGA-LIHC) using bioinformatics methods. They revealed that CDCA2 is an independent prognostic biomarker in HCC, and enhanced expression of CDCA2 is correlated with the up-regulation of immune checkpoints [ 17 ]. However, the exact role of CDCA2 on the malignant growth of HCC cell has not been studied.…”