Senescence-associated miRNAs predict survival and modulate the tumor immune microenvironment via SPOCK1 targeting in clear cell renal cell carcinoma.

Abstract

Background: Clear cell renal cell carcinoma(ccRCC) is a highly aggressive urological malignancy originating from proximal tubular epithelial cells. Celluar senescence plays a pivotal role in tumorigenesis and shaping the immune landscape. MicroRNAs (miRNAs) are essential regulators of tumor metabolism and biological behavior, and identifying senescence-associated miRNA (CS-miRNA) signatures is critical for improving prognosis and guiding treatment strategies.

Methods: We proformed multiomics analysis on 616 ccRCC samples from the TCGA-KIRC dataset and developed a CS-miRNA-based scoring system(CS-miRNAs-Score) using machine learning algorithms to evaluate clinical and immunological characteristics. The model was externally validated with miRNA-seq data from 21 clinical ccRCC samples. Based on CS-miRNA expression profiles, patients were stratified into two distinct clusters with significantly different clinical outcomes, mutation profiles,and biological pathways.

Results: The CS-miRNAs-Score,comprising 10 prognostically relevant miRNAs, was significantly associated with overall survival, immune and stromal scores, immune checkpoint expression response to immunotherapy. In addition, we constructed a miRNA-mRNA interaction network and experimentally validated the tumor-suppressive role of hsa-miR-130a-3p in ccRCC. Functional assays, including CCK-8, Transwell migration, scratch wound healing, and dual-luciferase reporter assays, confirmed that has-miR-130a-3p directly binds to and inhibits SPOCK1, an oncogene in ccRCC.

Conclusions: Our findings highlight the prognostic and therapeutic relevance of senescence-associated miRNAs in ccRCC, providing novel biomarkers and potential targets for personalized immunotherapy.