Chen Liuyan, Wu Lvying, Tang Minying, Cheng Yuanhang, Wang Kuanyin, Zhang Jianan, Deng Wenyi, Zhu Lingfeng, Chen Jin
Institute of Clinical Medicine, The Second affiliated Hospital of Hainan Medical University, 368th Yehai Avenue, Haikou, Hainan, 570311, China.
Fujian Provincial Key Laboratory of Transplant Biology, 900th Hospital, Fuzhou, Fujian, 350025, China.
BMC Urol. 2025 Jan 16;25(1):8. doi: 10.1186/s12894-025-01694-x.
Clear cell renal cell carcinoma (ccRCC) is the most common malignant urological tumor, and regrettably, and is insensitive to chemotherapy and radiotherapy, resulting in poor patient outcomes. DBF4 plays a critical role in DNA replication and participates in various biological functions, making it an attractive target for cancer treatment. However, its significance in ccRCC has not yet been explored.
We utilized external datasets and bioinformatics analyses to investigate the significance of DBF4 in ccRCC. We analysed its expression patterns, prognostic and diagnostic value, and potential mechanisms. We subsequently validated our findings through an immunohistochemistry (IHC) assay of ccRCC clinical samples. We further investigated the impact of DBF4 on the progression of ccRCC cells. Various assays, including assessments of cell proliferation, apoptosis, the cell cycle, cell migration and invasion, and colony formation, and xenograft tumor models were subsequently performed following to the knockdown of DBF4 expression via shRNA.
Bioinformatics analyses revealed that DBF4 is significantly overexpressed in ccRCC tissues compared with adjacent normal tissues. This overexpression was confirmed by IHC analysis of 75 pairs of clinical ccRCC tumor and adjacent tissues. Kaplan-Meier analysis revealed that high DBF4 expression was associated with a significantly lower five-year overall survival rate. Moreover, DBF4 expression was identified as an independent risk factor in multivariate Cox regression analysis. GO and KEGG pathway enrichment analyses revealed a substantial enrichment of terms associated with cell division, whereas gene set enrichment analysis (GSEA) revealed correlations between increased DBF4 expression and the activation of cell cycle-related pathways. Subsequent in vitro and in vivo experiments demonstrated that DBF4 knockdown in ccRCC cells not only suppressed proliferation and migration in vitro but also significantly inhibited tumor growth in xenograft mice by arresting the cell cycle at the G1/G0 phase, which was mediated by the inhibition of MCM2 phosphorylation and cyclin D1 and CDK4 expression.
The current study revealed that DBF4 overexpression is a significant factor associated with malignant features and poor prognosis in patients with ccRCC. Therefore, it was proposed that DBF4 could serve as a novel potential prognostic biomarker and molecular target for ccRCC.
Not applicable.
透明细胞肾细胞癌（ccRCC）是最常见的泌尿系统恶性肿瘤，遗憾的是，它对化疗和放疗不敏感，导致患者预后较差。DBF4在DNA复制中起关键作用，并参与多种生物学功能，使其成为有吸引力的癌症治疗靶点。然而，其在ccRCC中的意义尚未得到探索。
我们利用外部数据集和生物信息学分析来研究DBF4在ccRCC中的意义。我们分析了其表达模式、预后和诊断价值以及潜在机制。随后，我们通过对ccRCC临床样本进行免疫组织化学（IHC）检测来验证我们的发现。我们进一步研究了DBF4对ccRCC细胞进展的影响。在通过shRNA敲低DBF4表达后，随后进行了各种检测，包括细胞增殖、凋亡、细胞周期、细胞迁移和侵袭以及集落形成评估，以及异种移植肿瘤模型。
生物信息学分析显示，与相邻正常组织相比，DBF4在ccRCC组织中显著过表达。对75对临床ccRCC肿瘤组织和相邻组织的IHC分析证实了这种过表达。Kaplan-Meier分析显示，高DBF4表达与显著较低的五年总生存率相关。此外，在多变量Cox回归分析中，DBF4表达被确定为独立危险因素。GO和KEGG通路富集分析显示与细胞分裂相关的术语大量富集，而基因集富集分析（GSEA）显示DBF4表达增加与细胞周期相关通路的激活之间存在相关性。随后的体外和体内实验表明，ccRCC细胞中DBF4的敲低不仅抑制了体外增殖和迁移，还通过将细胞周期阻滞在G1/G0期显著抑制了异种移植小鼠中的肿瘤生长，这是由MCM2磷酸化以及细胞周期蛋白D1和CDK4表达的抑制介导的。
当前研究表明，DBF4过表达是与ccRCC患者恶性特征和不良预后相关的重要因素。因此，有人提出DBF4可作为ccRCC的一种新的潜在预后生物标志物和分子靶点。
不适用。
