{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMiR‐219A2 and its mature transcript isoforms play multifaceted roles in regulating cellular proliferation, differentiation, and apoptosis across both the nervous system and various human cancers. In the central nervous system, miR‐219 is critical for neurodevelopment and myelin formation. In neural stem cells, TLX—a key nuclear receptor for proliferation and self‐renewal—suppresses miR‐219 processing, and aberrant miR‐219 upregulation is linked to reduced stem cell proliferation observed in schizophrenia patient–derived cells (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "]). Furthermore, decreased miR‐219 expression in multiple sclerosis lesions correlates with failed oligodendrocyte differentiation and impaired remyelination, while in temporal lobe epilepsy, an inverse relationship between miR‐219 and NMDA receptor expression implicates it in the regulation of excitatory neurotransmission (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, miR‐219A2—often detected as miR‐219a-5p—functions predominantly as a tumor suppressor by targeting key oncogenic pathways. In triple-negative breast cancer, miR‐219a-5p is sequestered by the long noncoding RNA HCP5, leading to upregulation of anti-apoptotic BIRC3 and promoting tumor progression (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "]). A similar tumor-suppressive role has been observed in esophageal squamous cell carcinoma and epithelial ovarian cancer, where reduced miR-219a-5p levels are associated with enhanced proliferation, migration, invasion, and activation of pro-tumorigenic pathways such as those governed by Twist and the Wnt/β-catenin axis (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "]). In ovarian cancer, the MEG3/miR‐219a-5p/EGFR axis further emphasizes its role in restraining malignant cell behaviors (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "]). Additionally, in breast cancer metastasis, higher miR‐219a-5p expression is linked to reduced epithelial‐mesenchymal transition via repression of MRTF-A, and in non-small cell lung carcinoma, its upregulation enhances radiosensitivity by targeting CD164 and promoting apoptotic DNA damage responses (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond development and oncogenesis, miR‐219 isoforms contribute importantly to the regulation of inflammation and tissue repair. In human macrophages, the miR-219-2 arm is selectively active, modulating leukotriene B4 production and the synthesis of specialized pro-resolving mediators, thereby influencing the resolution phase of inflammation—a response further modulated by apoptotic neutrophils (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "]). In models of traumatic brain injury, elevated miR‐219a-5p suppresses targets such as CCNA2 and CACUL1 to regulate the Akt/Foxo3a and p53/Bcl-2 pathways, ultimately promoting neuronal apoptosis and offering potential as a biomarker of injury severity (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "]). Moreover, in keratinocytes, miR‐219-5p targets TMEM98 to negatively regulate cell migration and wound healing, and its specific cleavage by immunoglobulin G abzymes in human milk may suggest a unique regulatory mechanism operative in neonatal immunity (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kiyohito Murai, Guoqiang Sun, Peng Ye, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Regulator of oligodendrocyte maturation, miR-219, a potential biomarker for MS."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neuroinflammation (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12974-017-1006-3"}], "href": "https://doi.org/10.1186/s12974-017-1006-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29202778"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29202778"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Osmi Hamamoto, Daniela Pretti da Cunha Tirapelli, Fermino Sanches Lizarte Neto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Modulation of NMDA receptor by miR-219 in the amygdala and hippocampus of patients with mesial temporal lobe epilepsy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Neurosci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jocn.2020.02.024"}], "href": "https://doi.org/10.1016/j.jocn.2020.02.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32111564"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32111564"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Lihong Wang, Tian Luan, Shunheng Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LncRNA HCP5 promotes triple negative breast cancer progression as a ceRNA to regulate BIRC3 by sponging miR-219a-5p."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Med (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cam4.2335"}], "href": "https://doi.org/10.1002/cam4.2335"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31215169"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31215169"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Qiang Ma "}, {"type": "b", "children": [{"type": "t", "text": "MiR-219-5p suppresses cell proliferation and cell cycle progression in esophageal squamous cell carcinoma by targeting CCNA2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Biol Lett (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s11658-018-0129-6"}], "href": "https://doi.org/10.1186/s11658-018-0129-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30766610"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30766610"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Chunyan Wei, Xi Zhang, Sai He, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-219-5p inhibits the proliferation, migration, and invasion of epithelial ovarian cancer cells by targeting the Twist/Wnt/β-catenin signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2017.09.012"}], "href": "https://doi.org/10.1016/j.gene.2017.09.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28890378"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28890378"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Lei Wang, Mingxin Yu, Shanshan Zhao "}, {"type": "b", "children": [{"type": "t", "text": "lncRNA MEG3 modified epithelial-mesenchymal transition of ovarian cancer cells by sponging miR-219a-5p and regulating EGFR."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biochem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcb.29037"}], "href": "https://doi.org/10.1002/jcb.29037"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31161607"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31161607"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Chunyu Zhuang, Ying Yuan, Tiefeng Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-219a-5p inhibits breast cancer cell migration and epithelial-mesenchymal transition by targeting myocardin-related transcription factor A."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Biochim Biophys Sin (Shanghai) (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/abbs/gmx114"}], "href": "https://doi.org/10.1093/abbs/gmx114"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29077787"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29077787"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Tao Wei, Shan Cheng, Xiao Na Fu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-219a-5p enhances the radiosensitivity of non-small cell lung cancer cells through targeting CD164."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biosci Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BSR20192795"}], "href": "https://doi.org/10.1042/BSR20192795"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32364222"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32364222"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Gabrielle Fredman, Yongsheng Li, Jesmond Dalli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Self-limited versus delayed resolution of acute inflammation: temporal regulation of pro-resolving mediators and microRNA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep00639"}], "href": "https://doi.org/10.1038/srep00639"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22957142"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22957142"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jing Yan, Xiaomin Bu, Zhuoling Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Screening the expression of several miRNAs from TaqMan Low Density Array in traumatic brain injury: miR-219a-5p regulates neuronal apoptosis by modulating CCNA2 and CACUL1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurochem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jnc.14717"}], "href": "https://doi.org/10.1111/jnc.14717"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31077370"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31077370"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Q Tang, H Ran "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-219-5p inhibits wound healing by targeting TMEM98 in keratinocytes under normoxia and hypoxia condition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Rev Med Pharmacol Sci (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.26355/eurrev_201810_16026"}], "href": "https://doi.org/10.26355/eurrev_201810_16026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30338788"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30338788"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Ivan Yu Kompaneets, Evgeny A Ermakov, Sergey E Sedykh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IgGs from Human Milk Hydrolyze microRNAs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Molecules (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/molecules25102366"}], "href": "https://doi.org/10.3390/molecules25102366"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32443717"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32443717"}]}]}]}