Objectives: Prostate cancer (PCa) is a highly prevalent male malignancy with limited efficacy in advanced stages. Dysregulated modulation of necroptosis was reported to be tightly correlated with PCa initiation and progression. Herein, we aimed to identify necroptosis-associated long non-coding RNAs (lncRNAs) and delineate their functional roles in PCa through an integrated approach combining bioinformatic analyses and in vitro experimental validation. Methods: RNA sequencing data and corresponding clinical information of PCa were downloaded from The Cancer Genome Atlas (TCGA). Differentially expressed necroptosis-related genes (NRGs) and lncRNAs were screened, and necroptosis activity was assessed by single-sample gene set enrichment analysis (ssGSEA). Weighted Gene Co-expression Network Analysis (WGCNA) identified necroptosis-related lncRNA modules, with key lncRNAs prioritized via Cox regression. Clinical correlation analyses and in vitro experiments validated the function of the key lncRNA LINC00595. Results: A total of 50 differentially expressed NRGs were identified, among which pro-necroptotic genes exhibited pronounced downregulation, while anti-necroptotic genes were significantly upregulated. Consistently, ssGSEA confirmed reduced necroptosis activity in PCa. WGCNA further identified 13 core necroptosis-related lncRNAs (NRlncRNAs), with Cox regression analysis pinpointing LINC00595 and LINC00908 as the top prognostic candidates. Both lncRNAs were downregulated in PCa, with low expression correlating with advanced T stage, lymph node metastasis, and poor prognosis. Functional experiments demonstrated that LINC00595 overexpression inhibited PCa cell proliferation, migration, and invasion, and enhanced necroptosis. Conclusions: Collectively, our findings identified LINC00595 and LINC00908 as novel regulators of necroptosis in PCa. Specifically, LINC00595 exerted tumor-suppressive effects by enhancing necroptosis, holding potential as prognostic biomarkers and therapeutic targets.
Tang et al. (Thu,) studied this question.