Loss of tissue specificity and recurrent pan-cancer activation define a conserved oncogenic microRNA class

MicroRNAs (miRNAs) act as crucial post-transcriptional regulators of large gene networks, and their aberrant expression drives key oncogenic processes such as epithelial-mesenchymal transition (EMT), angiogenesis, immune evasion, and metastasis. Oncogenic miRNAs that lose tissue specificity during malignant transformation represent promising therapeutic targets, as their restricted expression in healthy organs could minimize off-target effects. To identify these candidates, this study performed a comprehensive pan-cancer analysis integrating tissue-specificity profiles of healthy tissues from the GTEx project with tumor data from the TCGA, TARGET, CGCI, and CPTAC cohorts. By combining profiling with differential expression analysis between tumor and matched normal samples, cross-cohort integration revealed that malignant transformation is characterized by a widespread loss of tissue-specific miRNA expression. Among these altered patterns, a cluster of nine oncomiRs was identified: miR-105-5p, miR-1269a, miR-196a-5p, miR-9-5p, miR-96-5p, miR-210-3p, miR-301b-3p, miR-592, and miR-135b-5p. These specific miRNAs were significantly and recurrently upregulated across various solid tumors. Functional enrichment analysis of their experimentally validated targets demonstrated a clear convergence on shared oncogenic pathways, particularly those governing hypoxia response, PI3K/AKT signaling, EMT, angiogenesis, and immune modulation. Author SummaryMicroRNAs are tiny molecules in our cells that act like master switches, capable of adjusting entire networks of genes at once. Because they have such powerful control, cancer cells often hijack them to grow and spread throughout the body. Normally, many microRNAs are highly specialized, operating only in specific organs to maintain healthy tissue function. In this study, we looked across thousands of patient samples from various cancer types to see what happens to this specialization during tumor development. We discovered that when healthy cells transform into cancer, they lose this strict tissue-specific control. Specifically, we identified a group of nine microRNAs that break free from their normal boundaries and become active in tumors where they shouldnt be. Crucially, these nine molecules are responsible for turning on traits that are essential for tumor growth. Since these microRNAs are normally restricted to very specific healthy tissues, targeting them in tumors where they have gone rogue could become a precise and valuable strategy to halt cancer progression while potentially minimizing side effects in the rest of the body.