Emerging roles of PIWI-interacting RNAs in cancer molecular diagnostics and therapeutics: a molecular biosciences perspective

Cancer claims nearly 10 million lives yearly, demanding innovative diagnostics and therapies beyond surgery and chemotherapy’s limitations, such as resistance and toxicity. Next-generation sequencing has unveiled PIWI-interacting RNAs (piRNAs), 26–31 nucleotide small non-coding RNAs, as pivotal regulators in cancer pathogenesis, offering fresh biomarkers and targets from a molecular biosciences lens. Once deemed germline-exclusive for transposon silencing via PIWI proteins (PIWIL1-4), piRNAs exhibit somatic dysregulation across malignancies, driving hallmarks like proliferation, metastasis, and chemoresistance. In colorectal cancer, piR-823 fosters invasion by stabilizing HIF-1α and G6PD, correlating with poor prognosis. Gastric cancers overexpress piR-651, promoting G2/M arrest evasion; lung cancers feature PMLCPIR enhancing ITGB1-PI3K-AKT signaling; multiple myeloma leverages piR-823 for proliferation; and hepatocellular carcinoma shows PIWIL1 upregulation tied to stemness. PiRNAs’ tissue-specific signatures enable liquid biopsy detection, with panels predicting recurrence-free survival (e.g., piR-54265/STAT3 axis in CRC). Therapeutically, piRNA mimics/inhibitors (e.g., LNA-antisense against piR-L-138 in lung squamous cell carcinoma) sensitize tumors to cisplatin, while PIWI knockdown curbs metastasis preclinically. This review dissects piRNA biogenesis, oncogenic/suppressive duality, and translational promise. By bridging molecular mechanisms to clinical utility, encompassing diagnostics via plasma profiling and therapeutics like nanoparticle-delivered piRNA therapeutics, piRNAs herald a paradigm shift in precision oncology.