{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have revealed that miR‐216a plays a multifaceted role in cancer, acting as either an oncogene or tumor suppressor depending on the cellular context. In hepatocellular carcinoma, for example, the miR‐216a/217 cluster is up‐regulated and drives epithelial–mesenchymal transition, stem‐like properties, metastasis and sorafenib resistance by directly targeting tumor suppressors such as PTEN and SMAD7, while androgen‐mediated activation of MIR216A contributes to early hepatocarcinogenesis by repressing TSLC1. In lung and cervical cancers, tumor‐derived long noncoding RNAs (lncRNAs) such as DANCR and SNHG16 sequester miR‐216a‐5p to relieve repression of oncogenic targets (including BCL‑2, KLF12 and ZEB1), whereas in osteosarcoma and colorectal cancer forced expression of miR‐216a inhibits cell proliferation, migration and invasion by targeting CDK14 and KIAA1199. In pancreatic cancer, diminished miR‐216a expression has been associated with radio‑ and chemoresistance through failure to suppress targets such as beclin‑1 and JAK2/STAT3 signaling, while in non–small‑cell lung, oral squamous, gastric and esophageal cancers miR‑216a (or its variant miR‑216a‑3p) modulates proliferation, invasiveness and metabolic reprogramming by targeting factors including YB‑1, EIF4B, RUNX1 and TPT1. In uveal melanoma and prostate cancer, miR‑216a‐5p exerts tumor‑suppressive effects by regulating HK2 and JAK2 respectively."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond cancer, miR‐216a has emerged as a key regulator in non‐malignant disease processes. In vascular endothelial cells, increased miR‐216a during aging suppresses autophagy by targeting Beclin1, thereby promoting ox‑LDL–mediated endothelial dysfunction, while in models of atherosclerosis and ischemic stroke its up‐regulation exacerbates inflammation through interference with the Smad3/IκBα pathway. In models of diabetic retinopathy, miR‑216a contributes to retinal microvascular endothelial cell injury via modulation of NOS2 and the JAK/STAT pathway, and in asthma lower levels of miR‑216a‐5p are associated with greater epithelial injury owing to loss of HMGB1 repression. Moreover, circulating miR‑216 has been investigated as a potential biomarker in conditions such as chronic kidney disease, acute pancreatitis and even syphilitic inflammation, indicating its broad diagnostic utility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its direct actions on target mRNAs, the biological impact of miR‐216a is further refined by complex competitive endogenous RNA (ceRNA) interactions. Certain lncRNAs—notably DANCR, HOXA‑AS2, MALAT1 and OIP5‑AS1—act as “sponges” that sequester miR‑216a‐5p, thereby neutralizing its tumor‑suppressive functions and contributing to chemoresistance or enhanced tumor stemness in lung, hepatocellular and cervical cancers. Novel strategies employing engineered oncolytic adenoviruses have even incorporated artificial miR‑216a target sites to improve tumor selectivity, while recent work in renal cell carcinoma implicates miR‑216a‐5p in sensitizing tumors to treatment by modulating USP1, survivin and DR5. Furthermore, ceRNA networks involving DANCR have been observed in non–small‑cell lung cancer, underscoring the therapeutic potential of targeting the DANCR/miR‑216a axis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "39", "end_ref": "45"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Po-Jen Chen, Shiou-Hwei Yeh, Wan-Hsin Liu, et al. 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