{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMIR376A1, a member of the miR‐376 family, has been identified in circulating samples from patients with various cancers. For example, its altered expression was found among a panel of downregulated microRNAs in metastatic prostate cancer and in the plasma of breast cancer patients, suggesting its potential utility as a non‐invasive diagnostic biomarker in these malignancies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn hepatocellular carcinoma, MIR376A1 is frequently downregulated, and its loss correlates with enhanced proliferation and decreased apoptosis in liver cancer cells. Mechanistic investigations have revealed that MIR376A1 directly targets p85α (PIK3R1), thereby functioning as a tumor suppressor whose decrease may contribute to hepatocarcinogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSimilar tumor‐suppressive roles for MIR376A1 have been reported in several other cancer types. In osteosarcoma, studies show that downregulation of MIR376A1 not only contributes to tumor growth but is also involved in a regulatory axis with long non‐coding RNAs such as MALAT1, resulting in increased expression of growth‐promoting factors like TGFA. Additionally, in osteosarcoma and acute myeloid leukemia, MIR376A1 suppresses oncogenic phenotypes by targeting genes such as SATB1 and MT1X, while in gastric cancer, its negative regulation of TET1 and HIF‐1A influences PD‐L1 expression and drug resistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn retinoblastoma, MIR376A1 appears to modulate apoptosis. Experimental overexpression of MIR376A1 in retinoblastoma cells diminished the levels of caspase‐3 protein and reduced arsenic trioxide–induced apoptosis, whereas its inhibition led to increased caspase‐3 expression and aggravated cell death. This evidences a context‐dependent role in regulating apoptotic pathways under treatment conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the realm of lung cancers and other head–neck malignancies, distinct isoforms of MIR376A (such as miR‐376a‐5p) have been shown to influence cellular proliferation, migration, and apoptosis. In non–small cell lung cancer, downregulation of MIR376A‐5p alleviates its suppression of anti–oncogenic factors (e.g. via the TRIM36/RAD51 axis), while in laryngocarcinoma, circRNA–mediated sequestration of MIR376A contributes to drug resistance and cell survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond cancer, MIR376A1 plays a role in normal physiological processes. In studies of early human erythropoiesis, MIR376A1 was found to be abundantly expressed in progenitor cells where it targets key regulators such as cyclin‐dependent kinase 2 and Argonaute 2. This regulation maintains a lower rate of differentiation until its downregulation permits progression into mature erythroid lineages."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, aberrant levels of MIR376A1 have been implicated in neurodegenerative conditions including Parkinson’s disease. In patient-derived samples and cellular models, altered MIR376A1 expression was inversely correlated with mitochondrial regulators such as PGC1α and TFAM, suggesting that its dysregulation may contribute to mitochondrial dysfunction and disease progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "A Formosa, E K Markert, A M Lena, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNAs, miR-154, miR-299-5p, miR-376a, miR-376c, miR-377, miR-381, miR-487b, miR-485-3p, miR-495 and miR-654-3p, mapped to the 14q32.31 locus, regulate proliferation, apoptosis, migration and invasion in metastatic prostate cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2013.451"}], "href": "https://doi.org/10.1038/onc.2013.451"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24166498"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24166498"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Katarina Cuk, Manuela Zucknick, Dharanija Madhavan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plasma microRNA panel for minimally invasive detection of breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0076729"}], "href": "https://doi.org/10.1371/journal.pone.0076729"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24194846"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24194846"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yongxia Zheng, Lei Yin, Huan Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-376a suppresses proliferation and induces apoptosis in hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2012.05.054"}], "href": "https://doi.org/10.1016/j.febslet.2012.05.054"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22684007"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22684007"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yongxia Zheng, Huan Chen, Manxiang Yin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiR-376a and histone deacetylation 9 form a regulatory circuitry in hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Physiol Biochem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000369733"}], "href": "https://doi.org/10.1159/000369733"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25613642"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25613642"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Wei Luo, Hongbo He, Wenfeng Xiao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MALAT1 promotes osteosarcoma development by targeting TGFA via MIR376A."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.10752"}], "href": "https://doi.org/10.18632/oncotarget.10752"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27458156"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27458156"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Guanghong Zhou, Hao Jiang, Liping Ma "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA‑376a inhibits cell proliferation and invasion in osteosarcoma via directly targeting SATB1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med Rep (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/mmr.2018.9344"}], "href": "https://doi.org/10.3892/mmr.2018.9344"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30085330"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30085330"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Ji Wang, Ziyang Yu, Jun Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LncRNA NUTM2A-AS1 positively modulates TET1 and HIF-1A to enhance gastric cancer tumorigenesis and drug resistance by sponging miR-376a."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cam4.3544"}], "href": "https://doi.org/10.1002/cam4.3544"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33089970"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33089970"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Xiangke Xin, Zheng Xu, Jia Wei, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiR-376a-3p increases cell apoptosis in acute myeloid leukemia by targeting MT1X."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biol Ther (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15384047.2022.2054243"}], "href": "https://doi.org/10.1080/15384047.2022.2054243"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35316152"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35316152"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Y Zhang, J H Wu, F Han, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Arsenic trioxide induced apoptosis in retinoblastoma cells by abnormal expression of microRNA-376a."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neoplasma (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4149/neo_2013_033"}], "href": "https://doi.org/10.4149/neo_2013_033"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23373993"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23373993"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Bo Feng, Ke Chen, Weiwei Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "circPGAM1 enhances autophagy signaling during laryngocarcinoma drug resistance by regulating miR-376a."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2020.10.063"}], "href": "https://doi.org/10.1016/j.bbrc.2020.10.063"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33121682"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33121682"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "ShanHai Yu, Wei Li, XiangDing Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRIM36 enhances lung adenocarcinoma radiosensitivity and inhibits tumorigenesis through promoting RAD51 ubiquitination and antagonizing hsa-miR-376a-5p."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2022.08.053"}], "href": "https://doi.org/10.1016/j.bbrc.2022.08.053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36058131"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36058131"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Fang Wang, Jia Yu, Gui-Hua Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of erythroid differentiation by miR-376a and its targets."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cr.2011.79"}], "href": "https://doi.org/10.1038/cr.2011.79"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21556037"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21556037"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Masoud Baghi, Mahsa Rostamian Delavar, Elaheh Yadegari, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Modified level of miR-376a is associated with Parkinson's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.14979"}], "href": "https://doi.org/10.1111/jcmm.14979"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31930701"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31930701"}]}]}]}