Wang Lizhen, Qu Wu, Yang Zhifu
Department of Pathology, School of Basic Medicine and Forensic Medicine, Baotou Medical College, Baotou, Inner Mongolia, China.
Department of Pathology, The First Affiliated Hospital of Baotou Medical College, Baotou, Inner Mongolia, China.
Front Oncol. 2025 Jul 3;15:1569782. doi: 10.3389/fonc.2025.1569782. eCollection 2025.
The incidence and mortality of uterine corpus endometrial carcinoma (UCEC) is increasing. Despite advances in diagnosis and treatment, the fundamental molecular mechanisms remain unclear to some extent. In this study, the role and clinical significance of Cyclin D2 (CCND2) in UCEC is discussed and explored.
The Infinium Methylation EPIC v2.0 BeadChip (935K chip) was utilized to analyze genomic DNA samples from four UCEC patients and four matched controls. Differentially methylated positions (DMPs) were identified, leading to the selection of the CCND2 gene as a candidate gene. Immunohistochemistry (IHC) was employed to validate the effects of CCND2 on UCEC. An analysis was conducted using the UALCAN and GSCA databases to compare the expression and methylation levels of the CCND2 gene promoter region between UCEC and adjacent normal tissues, as well as to explore the relationship between CCND2 expression and the methylation level of its gene promoter region. Subsequently, Cox regression and ROC analysis were performed with R software.
Through 935K chip detection, a total of 87,182 DMPs were identified in the whole genome of two groups. CCND2 was selected for further functional analysis. IHC results revealed that the positive expression of CCND2 in UCEC was significantly lower than in normal endometrial tissue (P < 0.05). TCGA datasets were analyzed to explore differential patterns involving mRNA and DNA methylation features associated with CCND2. The findings demonstrated a significant increase in the methylation level of CCND2 (P < 0.001), and a significant reduction in its mRNA expression (P < 0.001). Furthermore, the methylation level of the CCND2 gene promoter region exhibited a negative correlation with its mRNA expression (Cor. = -0.18, FDR = 0.018). Results from ROC analysis and survival analysis indicated that CCND2 expression was a prognostic indicator for UCEC (AUC = 0.956), with better survival in the high expression group (P = 0.0466).
The study shows that UCEC has significantly abnormal DNA methylation patterns and expression profiles. Hypermethylation of the CCND2 promoter may reduce CCND2 expression and participate in tumor occurrence and development in UCEC. Hence, CCND2 shows promise as a potential biomarker for diagnosing and prognosticating UCEC.
子宫体子宫内膜癌（UCEC）的发病率和死亡率正在上升。尽管在诊断和治疗方面取得了进展，但基本分子机制在一定程度上仍不清楚。在本研究中，探讨了细胞周期蛋白D2（CCND2）在UCEC中的作用及临床意义。
利用Infinium甲基化EPIC v2.0 BeadChip（935K芯片）分析4例UCEC患者和4例匹配对照的基因组DNA样本。鉴定出差异甲基化位点（DMP），从而选择CCND2基因作为候选基因。采用免疫组织化学（IHC）验证CCND2对UCEC的影响。使用UALCAN和GSCA数据库进行分析，比较UCEC与相邻正常组织之间CCND2基因启动子区域的表达和甲基化水平，并探讨CCND2表达与其基因启动子区域甲基化水平之间的关系。随后，使用R软件进行Cox回归和ROC分析。
通过935K芯片检测，两组全基因组共鉴定出87,182个DMP。选择CCND2进行进一步功能分析。IHC结果显示，CCND2在UCEC中的阳性表达明显低于正常子宫内膜组织（P < 0.05）。分析TCGA数据集以探索与CCND2相关的mRNA和DNA甲基化特征的差异模式。结果显示CCND2的甲基化水平显著升高（P < 0.001），其mRNA表达显著降低（P < 0.001）。此外，CCND2基因启动子区域的甲基化水平与其mRNA表达呈负相关（相关系数 = -0.18，FDR = 0.018）。ROC分析和生存分析结果表明，CCND2表达是UCEC的预后指标（AUC = 0.956），高表达组生存情况更好（P = 0.0466）。
该研究表明，UCEC存在明显异常的DNA甲基化模式和表达谱。CCND2启动子的高甲基化可能降低CCND2表达，并参与UCEC的肿瘤发生和发展。因此，CCND2有望成为诊断和预测UCEC的潜在生物标志物。
