AAAGUGC Seed-Containing miRNAs: Master Regulators of Cancer Pathways and Therapeutic Resistance

MicroRNAs have emerged as pivotal post-transcriptional regulators, orchestrating a myriad of cellular processes critical to both normal physiology and pathological conditions, particularly cancer. Among these, miRNAs containing the highly conserved AAAGUGC seed sequence have garnered significant attention due to their multifaceted roles in cancer progression, acting as both oncogenes and tumour suppressors across a wide spectrum of malignancies. This review delves deeply into the evolutionary significance of AAAGUGC seed-containing miRNAs, elucidating their conserved nature and intricate roles in the regulation of cancer-related gene expression networks. We focused on eight specific miRNAs- miR-17-5p, miR-20a-5p, miR-93-5p, miR-106a-5p, miR-106b-5p, miR-519d-3p, miR-526b-3p, and miR-20b-5p -each of which demonstrates context-dependent oncogenic or tumour-suppressive behaviour. Through an indepth exploration of the molecular mechanisms by which these miRNAs modulate critical pathways, we highlighted their capacity to influence essential processes, including cell proliferation, apoptosis, epithelial-to-mesenchymal transition (EMT), metastasis, and drug resistance, reflecting the complexity of their regulatory roles. Furthermore, we dissected the intricate interactions between these miRNAs and their downstream targets, showcasing their diverse contributions to the tumour microenvironment. The implications of miRNA dysregulation in chemotherapy resistance were also explored. In conclusion, AAAGUGC seed-containing miRNAs represent a complex and evolutionarily conserved family with implications in cancer biology. Their ability to modulate multiple oncogenic and tumour-suppressive pathways highlights their potential as therapeutic targets or biomarkers in the context of personalized cancer treatment strategies. This review provides a comprehensive depth of current knowledge while proposing avenues for future research into the therapeutic manipulation of these miRNAs in combating cancer.