{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMiR‐339 (predominantly the 5p strand, with evidence also for its 3p form) has emerged as a multifaceted regulator in both neurodegenerative and immunomodulatory contexts. In Alzheimer’s disease, reduced miR‐339‐5p levels lead to de‐repression of key targets such as BACE1, thereby promoting amyloid‐β peptide production and plaque formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In parallel, disruption of microRNA processing that downregulates miR‐339 is associated with elevated ICAM‐1 expression in tumor cells, influencing immune surveillance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, exosome‐derived miR‐339‐5p serves as a promising marker of radiosensitivity in esophageal cancer cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn various cancers, miR‐339‐5p acts largely as a tumor suppressor by targeting critical oncogenic regulators. It directly suppresses MDM2, thereby potentiating p53 function in cancer cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "and is similarly effective in colorectal cancer where its downregulation correlates with impaired p53 responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Its tumor‐suppressive capacity is further modulated by non‐coding RNAs: for example, in breast cancer, MALAT1 sponges miR‐339‐5p to affect downstream cellular responses"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", while MAFG‐AS1 similarly sequesters miR‐339‐5p in non‐small cell lung cancer to deregulate targets such as MMP15 that are critical for migration and invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In gastric cancer, miR‐339 suppresses cell migration and proliferation through inhibition of NOVA1"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", and in colon cancer, its targeting of DNMT3B results in re‐expression of tumor suppressor genes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Additional studies in hepatocellular and ovarian carcinomas reveal that elevated miR‐339‐5p levels curb invasion and metastatic traits"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", while exploratory work in gastric cancer further underscores its complex role."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond classical tumor suppression, miR‐339‐5p is implicated in diverse disease‐ and context‐specific pathways. In hematologic malignancies driven by aberrant FGFR1 activation (as in stem cell leukemia/lymphoma models), miR‐339‐5p is upregulated and promotes cell survival by mitigating proapoptotic gene expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Its regulation by circular RNAs, such as circ_0001795 in osteogenic cells, modulates YAP1 expression and thereby influences bone differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " In lung cancer, miR‐339 directly targets oncogenes including Skp2 and phosphatases like PRL‐1 to enhance the efficacy of radiotherapy"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ", with its elevated serum levels also offering promise as a non‐invasive diagnostic biomarker."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": " Preliminary studies extend its functional reach into cardiovascular disease, where miR‐339 may influence coronary heart disease pathogenesis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ", and into disorders affecting endothelial progenitor cells in polycystic ovary syndrome."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " In prostate cancer, deregulation of the circ_0005221/miR‐339‐5p/STAT5a axis has been linked to disease progression"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": ", while in glioma, miR‐339‐5p exerts inhibitory effects via the PTP4A1/HMGB1 pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " Its downregulation in schizophrenia appears to contribute to altered klotho gene expression and neuropsychiatric dysfunction"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": ", and in nasopharyngeal carcinoma, modulation of the miR‐339‐3p/KAT6A/TRIM24 axis affects epithelial–mesenchymal transition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": " Finally, in acute myeloid leukemia, miR‐339‐5p acts as an antiproliferative agent by targeting SOX4"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": ", while its targeting of Skp2 also contributes to growth inhibition in lung cancer.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Justin M Long, Balmiki Ray, Debomoy K Lahiri "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-339-5p down-regulates protein expression of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.518241"}], "href": "https://doi.org/10.1074/jbc.M113.518241"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24352696"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24352696"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Ryo Ueda, Gary Kohanbash, Kotaro Sasaki, et al. 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