前列腺组织的miRNA谱分析揭示了从良性经瘤周组织到肿瘤的分子连续谱

Background: Histologically, peritumoral tissue (PTT) or normal adjacent prostate tissue (NAT) surrounding tumors, is considered unaffected by the malignant process. However, emerging evidence suggests that the peritumoral microenvironment may harbor early molecular alterations. We hypothesize that PTT represents an intermediate molecular state between benign (BT) and tumor tissue (TT). Methods: Micro-RNA sequencing was performed on matched prostate tissues from 40 patients with prostate adenocarcinoma (after quality control 39 Tumor Tissues TT, 38 PTT, and 40 Benign Tissues BT). Differential miRNA expression (DEmiRNAs) was determined using DESeq2 (FDR ≤ 0.05), using BT as the reference group for the contrasts TT vs. BT and PTT vs. BT. Unsupervised principal component analysis (PCA), hierarchical clustering, fold-change comparisons, and pathway over-representation analysis of predicted miRNA targets (miRNet, KEGG/Reactome) were conducted. Results: PCA of global miRNA profiles revealed a molecular continuum along PC2 (18% of variance), with BT clustering at the negative extreme, TT at the positive extreme, and PTT distributed intermediately between both groups. Comparison of TT vs. BT identified 102 DEmiRNAs, while PTT vs. BT identified 57 DEmiRNAs. Remarkably, 39 miRNAs (68% of PTT vs. BT signature) were shared between both comparisons, and all 39 displayed concordant directional changes, indicating that a substantial fraction of the tumor-associated miRNA dysregulation is already present in PTT. Direct TT vs. PTT comparison revealed only 30 DEmiRNAs, confirming greater molecular similarity between TT and PTT than either with BT. Hierarchical clustering of the top 30 most significant TT vs. BT DEmiRNAs showed that PTT samples formed a distinct cluster with expression levels consistently intermediate between BT and TT, reinforcing the idea of a continuum molecular landscape between BT, PTT and TT. Pathway analysis of miRNA targets showed that nearly all significantly enriched pathways in PTT vs. BT were also altered in TT vs. BT, including key cancer-related pathways (e.g., tight junction, transcriptional dysregulation in cancer, chemical carcinogenesis-receptor activation). Magnitude analysis of the 39 shared DEmiRNAs confirmed stronger dysregulation in TT than PTT, consistent with progression along a continuum rather than an abrupt transition. Conclusions: miRNA profiling demonstrates that histologically PTT is molecularly altered and occupies an intermediate position between benign and fully malignant states. This molecular continuum supports the existence of a pre-malignant field effect driven by miRNA dysregulation and shared pathway alterations. These findings highlight PTT as a critical component of the tumor ecosystem and a potential source of early detection biomarkers or preventive therapeutic targets.