An Overview of the Crosstalk Dysregulation Between miRNAs and Signaling Pathways in Cancer: A Recent Perspective on Regulatory Networks

The discovery of microRNAs (miRNAs) has revolutionized the concept of posttranscriptional gene regulation. miRNAs play a significant role in regulating key signaling pathways for the maintenance of cellular homeostasis under physiological conditions. However, the cancerous state of the cell leads to the dysregulation of miRNA expression and its proper function due to genetic alterations, epigenetic remodeling, unusual transcriptional control, and defects in its biogenesis. A proper crosstalk between the intracellular signaling pathways and the miRNAs is significantly disrupted in cancer cells, leading to rewiring of oncogenic networks. In this review, an updated mechanism of miRNA biosynthesis and its dysregulation at each regulatory layer is elaborated. The functional consequences of defective miRNA biogenesis, including loss of tumor-suppressive miRNAs, amplification of oncogenic signaling, and acquisition of therapy resistance, are discussed. The functional consequences of the downregulated tumor-suppressive miRNA network and the upregulation of oncogenic signaling in core signaling pathways such as PI3K/AKT/mTOR, MAPK/RAS/ERK, Wnt/β-catenin, TGF-β/SMAD, JAK/STAT3, and Notch signaling are discussed. Moreover, the outcome of miRNA-signaling pathways, dysregulated crosstalk during epithelial–mesenchymal transition, metastasis, maintenance of cancer stem cells, and chemoresistance is highlighted. Furthermore, current challenges in targeting tumor-suppressive miRNAs and oncomiRs in cancer cells are highlighted. Besides this, the pioneering role of multiomics for the investigation of miRNA-regulated signaling is described. Collectively, this review features the understanding of miRNA-signaling crosstalk and its translational potential in precision oncology.