Ma Junjie, Qin Xin, Le Wei, Chen Xi, Wang Xiao, Xu Chengdang
Department of Urology, The Second Affiliated Hospital of Jiaxing University, 1518 North Huancheng Road, Jiaxing, 314000, Zhejiang, China.
Department of Urology, School of Medicine, Tongji Hospital, Tongji University, 389 Xincun Road, Shanghai,, 6000065, China.
Discov Oncol. 2024 Sep 27;15(1):496. doi: 10.1007/s12672-024-01373-7.
Prostate cancer (PCa) is a commonly occurring malignancy in elderly men. Olaparib, a poly ADP-ribose polymerase inhibitor, is utilized in PCa treatment. However, patients often develop resistance to olaparib after a period of treatment. Genetic alterations may play a significant role in this resistance, but the specific genes involved remain unclear. This study collected RNA-sequence data from the Gene Expression Omnibus database on both olaparib-sensitive and -resistant PCa cells to identify genes crucial for resistance. Subsequently, the enriched pathways of these genes were analyzed, and a protein-protein interaction (PPI) network was constructed to identify hub genes. The effect of these hub genes on PCa occurrence, progression, and prognosis was assessed using data from The Cancer Genome Atlas and Chinese Prostate Cancer Genome and Epigenome Atlas databases. Finally, this study validated our findings in clinical PCa samples and cells. From the GSE189186 dataset, 50 upregulated genes and 2 downregulated genes were identified in olaparib-resistant C4-2B and LNCaP cells. Utilizing the PPI network, eight upregulated genes (BBC3, TP53I3, FDXR, DDB2, CDKN1A, GADD45A, ZMAT3, and SESN1) were identified as hub genes for olaparib-resistant PCa cells. Furthermore, some of these genes were central to PCa occurrence, with BBC3 also influencing progression and prognosis. Importantly, BBC3 expression was upregulated in clinical PCa samples and affected PCa cells sensitive to olaparib, suggesting its potential as a predictive marker for PCa development and olaparib resistance.
前列腺癌（PCa）是老年男性中常见的恶性肿瘤。奥拉帕利是一种聚腺苷二磷酸核糖聚合酶抑制剂，用于PCa治疗。然而，患者在经过一段时间的治疗后往往会对奥拉帕利产生耐药性。基因改变可能在这种耐药性中起重要作用，但具体涉及的基因仍不清楚。本研究从基因表达综合数据库收集了奥拉帕利敏感和耐药PCa细胞的RNA序列数据，以确定对耐药至关重要的基因。随后，分析了这些基因的富集途径，并构建了蛋白质-蛋白质相互作用（PPI）网络以确定枢纽基因。使用来自癌症基因组图谱和中国前列腺癌基因组与表观基因组图谱数据库的数据评估这些枢纽基因对PCa发生、进展和预后的影响。最后，本研究在临床PCa样本和细胞中验证了我们的发现。从GSE189186数据集中，在奥拉帕利耐药的C4-2B和LNCaP细胞中鉴定出50个上调基因和2个下调基因。利用PPI网络，八个上调基因（BBC3、TP53I3、FDXR、DDB2、CDKN1A、GADD45A、ZMAT3和SESN1）被确定为奥拉帕利耐药PCa细胞的枢纽基因。此外，其中一些基因是PCa发生的核心，BBC3还影响进展和预后。重要的是，BBC3在临床PCa样本中的表达上调，并影响对奥拉帕利敏感的PCa细胞，表明其作为PCa发展和奥拉帕利耐药预测标志物的潜力。
