多学科方法的整合揭示了 PTGES3 是治疗乳腺癌的新药物靶点。
The integration of multidisciplinary approaches revealed PTGES3 as a novel drug target for breast cancer treatment.
机构信息
Precision Medicine Laboratory, School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, China.
School of Mathematics and Statistics, Henan University of Science and Technology, Luoyang, China.
出版信息
J Transl Med. 2024 Jan 20;22(1):84. doi: 10.1186/s12967-024-04899-0.
BACKGROUND
The main challenge in personalized treatment of breast cancer (BC) is how to integrate massive amounts of computing resources and data. This study aimed to identify a novel molecular target that might be effective for BC prognosis and for targeted therapy by using network-based multidisciplinary approaches.
METHODS
Differentially expressed genes (DEGs) were first identified based on ESTIMATE analysis. A risk model in the TCGA-BRCA cohort was constructed using the risk score of six DEGs and validated in external and clinical in-house cohorts. Subsequently, independent prognostic factors in the internal and external cohorts were evaluated. Cell viability CCK-8 and wound healing assays were performed after PTGES3 siRNA was transiently transfected into the BC cell lines. Drug prediction and molecular docking between PTGES3 and drugs were further analyzed. Cell viability and PTGES3 expression in two BC cell lines after drug treatment were also investigated.
RESULTS
A novel six-gene signature (including APOOL, BNIP3, F2RL2, HINT3, PTGES3 and RTN3) was used to establish a prognostic risk stratification model. The risk score was an independent prognostic factor that was more accurate than clinicopathological risk factors alone in predicting overall survival (OS) in BC patients. A high risk score favored tumor stage/grade but not OS. PTGES3 had the highest hazard ratio among the six genes in the signature, and its mRNA and protein levels significantly increased in BC cell lines. PTGES3 knockdown significantly inhibited BC cell proliferation and migration. Three drugs (gedunin, genistein and diethylstilbestrol) were confirmed to target PTGES3, and genistein and diethylstilbestrol demonstrated stronger binding affinities than did gedunin. Genistein and diethylstilbestrol significantly inhibited BC cell proliferation and reduced the protein and mRNA levels of PTGES3.
CONCLUSIONS
PTGES3 was found to be a novel drug target in a robust six-gene prognostic signature that may serve as a potential therapeutic strategy for BC.
背景
在乳腺癌（BC）的个体化治疗中，主要的挑战是如何整合大量的计算资源和数据。本研究旨在通过网络多学科方法，确定一种新的分子靶标，可能对 BC 的预后和靶向治疗有效。
方法
首先基于 ESTIMATE 分析鉴定差异表达基因（DEGs）。使用 TCGA-BRCA 队列中六个 DEGs 的风险评分构建风险模型，并在外部和临床内部队列中进行验证。随后，评估内部和外部队列中的独立预后因素。用 PTGES3 siRNA 瞬时转染 BC 细胞系后，进行细胞活力 CCK-8 和伤口愈合实验。进一步分析 PTGES3 与药物之间的药物预测和分子对接。还研究了两种 BC 细胞系在药物处理后细胞活力和 PTGES3 表达的变化。
结果
一个新的六基因特征（包括 APOOL、BNIP3、F2RL2、HINT3、PTGES3 和 RTN3）用于建立一个预后风险分层模型。风险评分是一个独立的预后因素，比单独的临床病理危险因素更能准确预测 BC 患者的总生存期（OS）。高风险评分有利于肿瘤分期/分级，但不利于 OS。在特征中的六个基因中，PTGES3 的风险比最高，其 mRNA 和蛋白水平在 BC 细胞系中显著增加。PTGES3 敲低显著抑制 BC 细胞增殖和迁移。三种药物（吉杜宁、染料木黄酮和己烯雌酚）被证实靶向 PTGES3，并且染料木黄酮和己烯雌酚的结合亲和力强于吉杜宁。染料木黄酮和己烯雌酚显著抑制 BC 细胞增殖，降低 PTGES3 的蛋白和 mRNA 水平。
结论
PTGES3 是一个稳健的六基因预后特征中的一个新的药物靶点，可能作为 BC 的潜在治疗策略。
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