Unravelling the nexus of non-coding RNAs in cancer stemness and therapeutic drug resistance

Cancer stem cells (CSCs) play a pivotal role in tumor initiation, progression, and therapy resistance. Emerging evidence suggests that non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), intricately regulate CSC properties. This article reviews current knowledge on the intricate interplay between ncRNAs, genetic and epigenetic factors having role in cancer stemness and associated phenotypes. We have also identified key stemness- and EMT-associated genes, including OCT4, SOX2, NANOG, KLF4, CD44, ALDH1A1, BMI1, ZEB1, ZEB2, SNAIL, SLUG, and TWIST1 that are regulated by ncRNAs in different cancer types. Additionally, we have described how ncRNA-mediated regulation of these genes influences major signaling pathways, including Wnt/β-catenin, Notch, Hedgehog, PI3K/AKT/mTOR, JAK/STAT, NF-κB, Hippo/YAP, and TGF-β signaling. The mir-21, miR-34, miR-200, and let-7 families target self-renewal and epithelial-to-mesenchymal transition while lncRNAs like H19, HOTAIR, and MALAT1 remodel the regulatory and epigenetic landscape of cancer stem cells. Understanding the interplay between ncRNAs and CSCs offers new insights into potential targeted therapies for combating aggressive and therapy-resistant cancers. Additionally, combining ncRNA interventions with conventional modalities such as chemotherapy, epigenetic drugs along with the advance nanotechnology-based drug delivery systems could result into synergistic outcomes. However, delivery, efficacy, and safety challenges remain. Overall, the ncRNA-cancer stemness interplay warrants therapeutic advancements and clinical translation towards a promising treatment personalization.