Mapping the miRNA Landscape of Gallbladder Cancer: Genome-Wide Insights and Functional Implications

Gallbladder cancer (GBC), the sixth most aggressive gastrointestinal cancer, exhibits complex molecular dysregulation involving microRNAs (miRNAs) that drive tumor progression. This study has comprehensively profiled genome-wide miRNA expression in GBC cells revealing 971 known miRNAs, and 27 novel miRNAs. We identified 388 significantly differentially expressed (DE) miRNAs (191 upregulated and 197 downregulated), providing valuable insights into the various complex molecular mechanisms underlying GBC pathogenesis. These DE miRNAs target key biological processes, including hormone-induced signaling pathways, cell adhesion molecules, apoptosis, ferroptosis, and cancer-associated pathways, particularly those linked to gastric cancer. Profiling of DE miRNAs in GBC cells presents opportunities for novel miRNA-based diagnostic and prognostic approaches in GBC. Notably, among the DE miRNAs, the miR-17~92 cluster was significantly suppressed in GBC cells. We also show that miR-17~92 cluster targets and destabilizes an S-phase licensing factor Cdt2 (an oncogene) in GBC cells. miR-17~92 mediated negative regulation of Cdt2 induces S-phase arrest, leading to checked proliferation and invasive capabilities of GBC cells specifically, without any significant effect on non-cancerous cells, presenting miR-17~92 as a potential miRNA therapeutic for GBC.