{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMicroRNA‐489 (miR-489) emerges as a multifaceted tumor suppressor in a wide range of human malignancies. Early profiling in head and neck cancers revealed a set of tumor‐suppressive miRNAs including miR-489, while investigations in ovarian, breast, pancreatic, colorectal, bladder, glioma, and hepatocellular carcinoma have consistently shown that reduced miR-489 levels correlate with enhanced proliferation, invasion, metastasis, and chemoresistance. Functional studies demonstrated that restoring miR-489 expression can inhibit cell growth, block epithelial–mesenchymal transition, and reverse resistance to conventional therapies through suppression of several oncogenes—including HER2, SPIN1, VAV3, BCL2, AKT3, Smad3, ADAM9, MMP7, TWIST1, PAX3, and JAG1—and through modulation of key signaling pathways such as PI3K/AKT and MAPK."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAn additional layer of regulation is imparted by noncoding RNAs that modulate miR-489 expression and function. Several long noncoding RNAs (lncRNAs) such as GSE1, ASLNC02525, and SNHG1 have been found to act as “sponges” that sequester miR-489 in breast, liver, and acute myeloid leukemia cells, respectively. In colorectal cancer, the lncRNA CHRF reduces miR-489 levels, while in non‐small cell lung cancer, lncRNA MIR503HG antagonizes miR-489’s tumor‐suppressive actions. Moreover, circular RNAs—for example, hsa_circ_0071036 in pancreatic ductal adenocarcinoma—have been shown to bind and inhibit miR-489, thereby contributing to oncogenic processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_fs", "start_ref": "16", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond cancer, miR-489 plays critical roles in non-malignant processes. During lung development, miR-489 is upregulated at the completion of alveolar septation, and its modulation has been implicated in compensatory mechanisms during hyperoxia-induced lung injury. In neural cells, elevated miR-489-3p levels contribute to increased apoptosis and impaired neurite outgrowth in experimental models of secondary spinal cord injury, acting at least in part via targeting NAA10 and activating the PI3K/AKT pathway. Similarly, in myocardial infarction models, increased miR-489 expression has been linked to enhanced cardiomyocyte apoptosis through downregulation of survival factors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, insights into miR-489’s mechanistic interplay with established signaling networks have uncovered novel therapeutic opportunities. In estrogen-receptor–positive breast cancer, miR-489 is directly regulated by estrogen and, in turn, negatively modulates ER signaling by attenuating MAPK and AKT activities and influencing ERα intracellular trafficking—a dynamic that disrupts positive feedback loops essential for tamoxifen resistance. Additionally, emerging evidence suggests that dysregulation of miR-489 may contribute to metabolic reprogramming in multiple myeloma. Collectively, these findings highlight miR-489 as a promising candidate for targeted therapeutic interventions across a spectrum of pathological conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "N Kikkawa, T Hanazawa, L Fujimura, et al. 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