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Abstract：
Background: Bladder cancer (BLCA) is the most common genitourinary malignancy. Proliferation essential genes (PEGs) are crucial to the survival of cancer cells. This study aimed to build a PEG signature to predict BLCA prognosis and treatment efficacy. Methods: BLCA PEGs and differentially expressed PEGs were identified using DepMap and TCGA-BLCA datasets, respectively. Based on the prognostic analysis of the differentially expressed PEGs, a PEG model was constructed. Subsequently, we analyzed the relationship between the PEG signature and prognosis of BLCA patients as well as their response to chemotherapy. Finally, we performed random forest analysis to target and functional experiments to validate the most significant PEG which is associated with BLCA progression. CCK-8, invasion, migration, and chemosensitivity assays were performed to assess effects of gene knockdown on BLCA cell proliferation, invasion and migration abilities, and cisplatin chemosensitivity. Results: We screened 10 prognostic PEGs from 201 differentially expressed PEGs and used them to construct a PEG signature model. Patients with high PEG signature score (PEGs-high) exhibited worse OS and lower sensitivity to chemotherapy than those with PEGs-low. We also found significant correlations between the PEG score and previously defined BLCA molecular subtypes. This suggests that the PEG score may effectively predict the molecular subtypes which have distinct clinical outcomes. Random forest analysis revealed that POLE2 (DNA polymerase epsilon subunit 2) was the most significant PEG differentiating BLCA tissue and normal tissue. Bioinformatic analysis and an immunohistochemistry staining assay confirmed that POLE2 was significantly up-regulated in tumor tissues and was associated with poor survival in BLCA patients. Moreover, POLE2 knockdown inhibited the ability of cell clone formation, proliferation, invasion, immigration and IC50 of cisplatin. Conclusion: The PEG signature acts as a potential predictor for prognosis and chemotherapy response in BLCA patients. POLE2 is a key PEG and plays a remarkable role in promoting the malignant progression and cisplatin resistance of BLCA.
摘要：
背景：膀胱癌（BLCA）是最常见的泌尿生殖系统恶性肿瘤。增殖必需基因(PEG)对癌细胞的存活至关重要。本研究旨在建立PEG标记来预测BLCA的预后和治疗效果。方法：使用DepMap和TCGA-BLCA数据集鉴定BLCAPEG和差异表达的PEG，分别。基于差异表达的PEG的预后分析，建立了PEG模型。随后，我们分析了PEG标记与BLCA患者预后及化疗反应的关系.最后,我们对目标和功能实验进行了随机森林分析,以验证与BLCA进展相关的最显著的PEG.CCK-8入侵,迁移,和化学敏感性测定进行评估基因敲低对BLCA细胞增殖的影响，入侵和迁移能力，和顺铂化疗敏感性。结果：我们从201个差异表达的PEG中筛选了10个预后PEG，并将其用于构建PEG签名模型。与PEG低的患者相比，PEG签名评分高（PEG高）的患者的OS更差，对化疗的敏感性更低。我们还发现PEG评分与先前定义的BLCA分子亚型之间存在显着相关性。这表明PEG评分可以有效地预测具有不同临床结果的分子亚型。随机森林分析表明，POLE2（DNA聚合酶ε亚基2）是最显著的PEG区分BLCA组织和正常组织。生物信息学分析和免疫组织化学染色测定证实,POLE2在肿瘤组织中显著上调,并且与BLCA患者的低生存率相关。此外，POLE2敲低抑制细胞克隆形成的能力,扩散,入侵,顺铂的移民和IC50。结论：PEG特征可作为BLCA患者预后和化疗反应的潜在预测指标。POLE2是一种关键的PEG，在促进BLCA的恶性进展和顺铂耐药方面发挥着重要作用。
