{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMIR9‐2 – one of the three independent genetic loci encoding microRNA‐9 – has emerged as a critical regulator of neural development. Studies in MIR9‐2/3 double‐mutant mice demonstrate that miR‐9 is required to modulate neural progenitor proliferation and differentiation in the developing telencephalon through fine‐tuning the expression of key transcription factors such as Foxg1, Pax6, and Meis2. In line with this, detailed promoter analyses have revealed that despite its intragenic location, MIR9‐2 is transcribed independently under the coordinated control of repressive and activating transcription factors (namely REST and CREB), establishing a feedback loop essential for neuronal differentiation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, deregulation of miR‐9 – often reflecting perturbations at loci including MIR9‐2 – contributes in a context‐dependent manner to tumor progression. In gastric cancer, for example, simultaneous hypermethylation of MIR9 promoters (miR‐9‐1, miR‐9‐2, and miR‐9‐3) leads to marked downregulation of miR‐9, bolstering its proposed tumor suppressor role. By contrast, in several other malignancies such as esophageal squamous cell carcinoma, oral squamous cell carcinoma, and certain breast tumors, aberrantly high levels of miR‐9 are associated with enhanced metastatic potential through the direct targeting of epithelial adhesion molecules and induction of epithelial–mesenchymal transition. In addition, miR‐9 has been implicated in the regulation of nuclear long non‐coding RNAs (e.g. MALAT1) as well as in mediating tumor cell sensitivity to chemoradiation, with further studies revealing that targeting key factors (such as UHRF1, ANO1, and components of the IL‐6/JAK/STAT3 signaling cascade) underlies its multifaceted roles in growth, migration, and invasion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond neurogenesis and oncogenesis, MIR9‐2–derived miR‐9 is increasingly recognized for its involvement in diverse pathological processes. In diabetic cardiomyopathy, for instance, miR‐9 targets an AU‐rich RNA‐binding protein (ELAVL1) to mitigate inflammation‐induced cardiomyocyte pyroptosis. Similarly, in certain hematologic malignancies such as acute myeloid leukemia, miR‐9 exerts tumor‐suppressive effects by inhibiting proliferative drivers. Its functional spectrum also extends to the modulation of hormone receptor status in breast cancer, the enhancement of radiosensitivity in non‐small cell lung cancer, and even the regulation of stress‐ and inflammation‐related pathways in mood disorders. Moreover, recent evidence indicates that miR‐9 packaged within exosomes from HPV‐positive head and neck tumors can reprogram tumor‐associated macrophages toward a proinflammatory, radiosensitive phenotype. Collectively, these studies underscore the versatile and context‐dependent nature of MIR9‐2 regulation, highlighting its promise as both a diagnostic biomarker and a therapeutic target across a wide spectrum of human diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Pietro Laneve, Ubaldo Gioia, Anastasia Andriotto, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Aberrant hypermethylation of miR-9 genes in gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Epigenetics (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/epi.6.10.16535"}], "href": "https://doi.org/10.4161/epi.6.10.16535"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21931274"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21931274"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Xin Zhou, Catalin Marian, Kepher H Makambi, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Up-regulation of miR-9 expression as a poor prognostic biomarker in patients with non-small cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Transl Oncol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12094-013-1106-1"}], "href": "https://doi.org/10.1007/s12094-013-1106-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24019037"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24019037"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "T Yu, K Liu, Y Wu, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Activation of miR-9 by human papillomavirus in cervical cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.2599"}], "href": "https://doi.org/10.18632/oncotarget.2599"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25344913"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25344913"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Ye Song, Jiangchao Li, Yinghui Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-9 promotes tumor metastasis via repressing E-cadherin in esophageal squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.2581"}], "href": "https://doi.org/10.18632/oncotarget.2581"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25375090"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25375090"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jiangbo Zhang, Junqiao Jia, Lijun Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Down-regulation of microRNA-9 leads to activation of IL-6/Jak/STAT3 pathway through directly targeting IL-6 in HeLa cell."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Carcinog (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/mc.22317"}], "href": "https://doi.org/10.1002/mc.22317"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25809226"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25809226"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Mingchen Zhu, Yijun Xu, Mengyuan Ge, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of UHRF1 by microRNA-9 modulates colorectal cancer cell proliferation and apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cas.12689"}], "href": "https://doi.org/10.1111/cas.12689"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25940709"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25940709"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Prince Jeyabal, Rajarajan A Thandavarayan, Darukeshwara Joladarashi, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-9 suppresses cell migration and invasion through downregulation of TM4SF1 in colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Oncol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijo.2016.3430"}], "href": "https://doi.org/10.3892/ijo.2016.3430"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26983891"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26983891"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Yueli Gu, Jinchun Si, Xichun Xiao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-92a Inhibits Proliferation and Induces Apoptosis by Regulating Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2) Expression in Acute Myeloid Leukemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3727/096504016X14829256525028"}], "href": "https://doi.org/10.3727/096504016X14829256525028"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28059050"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28059050"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Raffaela Barbano, Barbara Pasculli, Michelina Rendina, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Stepwise analysis of MIR9 loci identifies miR-9-5p to be involved in Oestrogen regulated pathways in breast cancer patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep45283"}], "href": "https://doi.org/10.1038/srep45283"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28345661"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28345661"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Lin Chen, Weifeng Hu, Guohao Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of miR-9-5p suppresses prostate cancer progress by targeting StarD13."}]}, {"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/s11658-019-0145-1"}], "href": "https://doi.org/10.1186/s11658-019-0145-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30899277"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30899277"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Ya-Chun Chen, Ming-Che Ou, Chia-Wei Fang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High Glucose Concentrations Negatively Regulate the IGF1R/Src/ERK Axis through the MicroRNA-9 in Colorectal Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cells (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/cells8040326"}], "href": "https://doi.org/10.3390/cells8040326"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30965609"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30965609"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Wei Wei, Zhuo Dong, Hui Gao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-9 enhanced radiosensitivity and its mechanism of DNA methylation in non-small cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2019.05.050"}], "href": "https://doi.org/10.1016/j.gene.2019.05.050"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31158449"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31158449"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Y-Q Wei, X-L Jiao, S-Y Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiR-9-5p could promote angiogenesis and radiosensitivity in cervical cancer by targeting SOCS5."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Rev Med Pharmacol Sci (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.26355/eurrev_201909_18837"}], "href": "https://doi.org/10.26355/eurrev_201909_18837"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31539118"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31539118"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Fangjia Tong, Xionghui Mao, Siwei Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HPV + HNSCC-derived exosomal miR-9 induces macrophage M1 polarization and increases tumor radiosensitivity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Lett (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.canlet.2020.02.037"}], "href": "https://doi.org/10.1016/j.canlet.2020.02.037"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32120025"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32120025"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Chenying Zheng, Chunxiao Bai, Qi Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Long noncoding RNA XIST regulates osteogenic differentiation of human bone marrow mesenchymal stem cells by targeting miR-9-5p."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mech Dev (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mod.2020.103612"}], "href": "https://doi.org/10.1016/j.mod.2020.103612"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32389806"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32389806"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Y Zhang, X-H Yao, Y Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LncRNA NEAT1 regulates pulmonary fibrosis through miR-9-5p and TGF-β signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Rev Med Pharmacol Sci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.26355/eurrev_202008_22661"}], "href": "https://doi.org/10.26355/eurrev_202008_22661"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32894569"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32894569"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Cancan He, Ying Bai, Zan Wang, et al. 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