{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nmiR‐204 is emerging as a multifunctional regulatory RNA with critical roles in normal development, vascular homeostasis and metabolism. In the pulmonary vasculature, for instance, reduced miR‐204 levels are linked to enhanced proliferation and resistance to apoptosis in smooth muscle cells—a key contributor to pulmonary arterial hypertension."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the eye, miR‐204 (often co‐expressed with miR‐211) is among the highest expressed microRNAs in the retinal pigment epithelium, where it maintains epithelial barrier properties by directly targeting regulators such as TGF‑β receptor 2 and SNAIL2; moreover, a mutation in its seed region has been implicated in familial ocular malformations including coloboma and photoreceptor degeneration"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " miR‐204 also contributes to metabolic control by directly suppressing the glucagon‐like peptide‐1 receptor in pancreatic β‑cells—a mechanism that, when relieved, enhances insulin secretion and improves glucose tolerance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In addition, during adipogenesis miR‐204–5p is up‐regulated and promotes differentiation by directly targeting DVL3 to dampen Wnt/β‑catenin signaling"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", while in the context of vascular calcification, its suppression via PARP1–IL‑6/STAT3 signaling has been shown to remove inhibitory constraints on osteogenic pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn various cancers miR‐204 predominantly functions as a tumor suppressor, with its down‐regulation correlating with disease progression, metastasis and drug resistance. In gastrointestinal malignancies such as renal cell, gastric and colorectal cancers, diminished miR‐204 levels release repression on oncogenic factors—including targets like LC3B, USP47, RAB22A, CREB1, and Bcl‑2—thereby favoring tumor growth, invasion, and chemoresistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "12"}]}, {"type": "t", "text": " In endometrial and papillary thyroid carcinomas, re‐expression of miR‐204 curtails migration, invasion and promotes apoptosis by targeting key transcription factors such as FOXC1 and insulin‑like growth factor–binding protein 5."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Its tumor‐suppressive role is further underscored in colorectal and hepatocellular cancers, where miR‐204 down‐regulation—often due to sequestration by long non‑coding RNAs (for example, UCA1, LINC01234, NEAT1, and ZEB2‑AS1)—leads to the derepression of oncogenic networks involving CBFB, glutaminase and HMGB1."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "18"}]}, {"type": "t", "text": " In gliomas and breast cancers, restoration of miR‐204 expression suppresses stem‐like traits, impairs proliferative and migratory capacities, in part by directly targeting factors such as RAB22A, SOX4, and PIK3CB."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " In nasopharyngeal and triple‑negative breast carcinomas, competing endogenous RNA mechanisms—via sponging of miR‑204 by lncRNAs (for instance, NEAT1 and ARNILA)—attenuate its ability to repress targets like ZEB1 and SOX4, ultimately promoting epithelial–mesenchymal transition and metastasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "23"}]}, {"type": "t", "text": " Notably, in melanoma, context‐dependent up‐regulation of miR‐204–5p has been linked to the development of resistance to BRAF inhibitors, acting through mechanisms that affect cell motility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": " Further underscoring its broad clinical relevance, analyses in plasma and tumor specimens from breast and other cancers reveal that low miR‑204 levels are significantly associated with adverse prognostic features and therapeutic resistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Fei E Wang, Connie Zhang, Arvydas Maminishkis, et al. 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