{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMiR‑663A is a multifaceted regulator in cancer, where its expression and function appear highly context‐dependent. In some malignancies such as gastric cancer, papillary thyroid carcinoma, hepatocellular carcinoma, colorectal cancer, and glioma, miR‑663A is downregulated and acts as a tumor suppressor by targeting several oncogenic mediators (for example, HMGA2, FSCN1, TTC22V1, and TGFB1) to inhibit cell proliferation, migration and invasion or to induce mitotic catastrophe. In contrast, in other cancer types including castration‐resistant prostate cancer, certain non‑small cell lung cancers, and breast carcinomas, miR‑663A is upregulated and promotes tumor progression by modulating cell cycle regulators (p53, p21), apoptotic pathways, and neuroendocrine differentiation. Moreover, recent studies have implicated epigenetic and post‑transcriptional mechanisms—such as promoter hypermethylation and m6A modification via METTL3—in fine‐tuning miR‑663A expression, underscoring its dual oncogenic and tumor‐suppressive roles depending on the cellular context."}, {"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": "\nBeyond cancer, miR‑663A plays important roles in vascular biology, inflammatory responses and immune regulation. In primary endothelial cells exposed to disturbed flow, miR‑663A is upregulated and contributes to an inflammatory gene network that enhances monocyte adhesion—a key early step in atherogenesis. In the kidney, miR‑663A participates in the regulation of renin and APOE messenger RNA levels, suggesting its involvement in blood‐pressure homeostasis and essential hypertension. Its aberrant expression also appears to modulate the phenotypic switch of vascular smooth muscle cells and to affect fibroblast‐like synoviocyte activation in rheumatoid arthritis. In addition, miR‑663A is a mediator of mesenchymal stem cell dysfunction in systemic lupus erythematosus and has been implicated in infection‐related epithelial apoptosis, thereby indicating a broader role in modulating inflammatory and immune‐related pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in proliferation and inflammation, miR‑663A is emerging as an important regulator of neural differentiation, metabolic homeostasis, and stress responses. In human neural stem cells, activation of the amyloid precursor protein intracellular domain leads to upregulation of miR‑663A that in turn suppresses the expression of neurogenesis‐associated genes, thereby negatively modulating neuronal differentiation. Furthermore, the miR‑663A promoter has been shown to be epigenetically regulated by mitochondria‑to‑nucleus retrograde signaling that influences the expression of nuclear‐encoded respiratory chain components and the assembly of mitochondrial supercomplexes. Consistent with these findings, miR‑663A expression is more strongly induced by oxidative stress in aged dermal fibroblasts and is further modulated by psychotropic agents such as fluoxetine in undifferentiated neural cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jian Pan, Hai Hu, Zhuan Zhou, et al. 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