关键词： ADT, androgen deprivation therapy AR, androgen receptor AUC, Area under the dose-response curve BCR, biochemical recurrence CAFs, cancer-associated fibroblasts CCLs, cancer cell lines CTLA-4, cytotoxic T-lymphocyte associated protein-4 DEmiRs, differentially expressed miRNAs DFS, disease-free survival EMT, epithelial-mesenchymal transition FDR, false discovery rate GEO, Gene Expression Omnibus GEP, gene expression profile GO, Gene Ontology GSEA, Gene Set Enrichment Analysis Heterogeneity ICB, immune checkpoint blockade IFN, interferon KEGG, Kyoto Encyclopedia of Genes and Genomes MDSCs, myeloid-derived suppressor cells MIRcor, miRNA-correlated Molecular subtypes NEPC, neuroendocrine prostate cancer NMF, non-negative matrix factorization NTP, Nearest template prediction OS, overall survival PCa, prostate cancer PD-1, programmed cell death protein-1 PD-L1, programmed death-ligand 1 Prostate cancer SCNAs, somatic copy number alterations SubMap, Subclass mapping TCGA, The Cancer Genome Atlas TGFβ, transforming growth factor β TMB, tumor mutation burden TNAs, tumor neoantigens Tregs, regulatory T cells k-NN, K-nearest neighbor mCRPC, metastatic castration-resistant prostate cancer miRNAs miRNAs, microRNAs ssGSEA, single-sample gene set enrichment analysis

来  源：   DOI：10.1016/j.csbj.2021.08.046   PDF(Sci-hub)   PDF(Pubmed)

Abstract：
MicroRNA (miRNA) deregulation plays a critical role in the heterogeneous development of prostate cancer (PCa) by tuning mRNA levels. Herein, we aimed to characterize the molecular features of PCa by clustering the miRNA-regulated transcriptome with non-negative matrix factorization. Using 478 PCa samples from The Cancer Genome Atlas, four molecular subtypes (S-I, S-II, S-III, and S-IV) were identified and validated in two merged microarray and RNAseq datasets with 656 and 252 samples, respectively. Interestingly, the four subtypes showed distinct clinical and biological features after comprehensive analyses of clinical features, multiomic profiles, immune infiltration, and drug sensitivity. S-I is basal/stem/mesenchymal-like and immune-excluded with marked transforming growth factor β, epithelial-mesenchymal transition and hypoxia signals, increased sensitivity to olaparib, and intermediate prognosis. S-II is luminal/metabolism-active and responsive to androgen deprivation therapy with frequent TMPRSS2-ERG fusion and a good prognosis. S-III is characterized by moderate proliferative and metabolic activity, sensitivity to taxane-based chemotherapy, and intermediate prognosis. S-IV is highly proliferative with moderate EMT and stemness, frequent deletions of TP53, PTEN and RB, and the poorest prognosis; it is also immune-inflamed and sensitive to anti-PD-L1 therapy. Overall, based on miRNA-regulated gene profiles, this study identified four distinct PCa subtypes that could improve risk stratification at diagnosis and provide therapeutic guidance.
摘要：
微小RNA(miRNA)失调通过调节mRNA水平在前列腺癌(PCa)的异质性发展中起关键作用。在这里，我们旨在通过非负矩阵分解对miRNA调节的转录组进行聚类来表征PCa的分子特征。使用来自癌症基因组图谱的478个PCa样本，四种分子亚型(S-I，S-II,S-III,和S-IV）在两个合并的微阵列和RNAseq数据集中的656和252个样本中进行了鉴定和验证，分别。有趣的是,4种亚型在综合分析临床特征后表现出明显的临床和生物学特征,多维配置文件，免疫浸润，和药物敏感性。S-I是基底/干/间充质样的，免疫排除有明显的转化生长因子β，上皮-间质转化和缺氧信号，增加对奥拉帕尼的敏感性，和中间预后。S-II具有腔/代谢活性，对雄激素剥夺治疗有反应，经常进行TMPRSS2-ERG融合，预后良好。S-III的特征是适度的增殖和代谢活性，对基于紫杉烷的化疗的敏感性，和中间预后。S-IV具有高度增生性，具有中等EMT和干性，频繁删除TP53、PTEN和RB，和最差的预后;它也是免疫发炎和敏感的抗PD-L1治疗。总的来说,基于miRNA调节的基因谱，这项研究确定了4种不同的PCa亚型,这些亚型可以改善诊断时的风险分层并提供治疗指导.
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