MicroRNAs in penile cancer: challenges, opportunities, and translational perspectives

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression, and dysregulated miRNA expression has been implicated in multiple cancer hallmarks. In penile cancer (PeCa), a rare but aggressive malignancy, evidence suggests that miRNAs contribute to tumor development and disease progression. This review aims to summarize the current understanding of miRNA involvement in PeCa, highlighting their potential as diagnostic, prognostic, and therapeutic biomarkers. A comprehensive review of published studies on miRNA expression in PeCa was performed, with an emphasis on molecular mechanisms, HPV association, clinical outcomes, and recent technological approaches, including high-throughput sequencing and bioinformatics-based analyses. Several miRNAs have been identified as differentially expressed in PeCa, associating with tumor aggressiveness, HPV infection, and patient prognosis. Despite these findings, most studies are descriptive, limited by small cohorts, and lack functional validation. Moreover, geographic disparities have been observed, with a concentration of studies in a few countries and an underrepresentation of high-incidence regions. Advances in omics technologies and the study of novel sources such as extracellular vesicles (EVs) have expanded the potential for identifying circulating miRNAs as non-invasive biomarkers. miRNAs represent promising tools for improving PeCa diagnosis, prognosis, and therapy. However, their clinical translation depends on larger, standardized, and functionally validated studies. In this context, integrating multi-omics and artificial intelligence approaches might accelerate biomarker validation and enable more precise, personalized management of PeCa.