Deciphering the clinical and epigenetic impact of oncomiR-221 through multi-omics integration: evidence from a pan-cancer systematic review and meta-analysis

MicroRNA-221 (miR-221) is an oncogenic miRNA that disrupts cell cycle regulation, induces resistance to apoptosis, and transcriptional silencing of tumor suppressor genes. We examined the multi-OMIC regulatory axes underlying the biological function of miR-221, which may serve as pan-cancer adverse prognostic factor and actionable therapeutic target in various tumor systems. A systematic review following the PRISMA criteria was conducted to highlight the association between miR-221 expression level and survival in PubMed, Google Scholar, and Dimensions databases. A meta-analysis of hazard ratios (HR) with 95% confidence intervals (CI) was performed using random-effects models and further stratified by cancer type, specimen type, and expression direction. Pan-cancer protein correlation was analyzed using the TCGA-LinkedOmics database and further assessed for TCGA-based concordance using cBioPortal. 28 studies were included in the meta-analysis. Higher miR-221 levels were correlated with poor overall survival (HR = 1.75), disease-free survival (HR = 1.85), and progression-free survival (HR = 2.11). Strong correlations were observed in glioma (HR = 2.13) and colorectal cancer (HR = 1.91). MiR-221 expression did not have a significant prognostic role in breast cancer. Subgroup analysis by specimen type showed no observed heterogeneity among plasma and blood/serum estimates (I² = 0%), whereas substantial heterogeneity was observed among tissue-based estimates (I² = 89.4%). Multidimensional omics profiling of six independent datasets from TCGA revealed that the most consistent correlation was an inverse relationship with tumor-suppressive proteins, with lower grade glioma (LGG) and liver hepatocellular carcinoma (LIHC) showing the strongest association. Concordant protein-level associations identified through TCGA-based analyses included SRC, VHL, EEF2, IRS1, AXL, and STAT5A, while TP53BP1 showed the strongest correlation in colorectal cancer. MiR-221 overexpression is associated with adverse prognosis across multiple cancer types and may contribute to tumor progression through context-dependent post-transcriptional regulation of cancer-related pathways, supporting further evaluation of miR-221 as a prognostic biomarker and therapeutic target.