{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMiR‑346 is dynamically regulated in response to cellular stress and inflammatory stimuli. In airway epithelial cells, endoplasmic reticulum stress induces miR‑346 via spliced X‑box–binding protein‑1, leading to downregulation of immune‐related mRNAs such as TAP1 and consequently reduced MHC class I antigen presentation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In rheumatoid arthritis fibroblast‐like synoviocytes, lipopolysaccharide stimulation elevates miR‑346 levels, which indirectly curtail the release of pro‐inflammatory cytokines such as interleukin‑18 and tumor necrosis factor‑α by targeting mediators like Bruton's tyrosine kinase and regulating TTP expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In the neural context, miR‑346 uniquely binds to the 5′‑UTR of amyloid‑β precursor protein mRNA to upregulate its translation, thereby potentially contributing to amyloid‑β peptide production in Alzheimer’s disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n \n \nIn various cancers miR‑346 exerts oncogenic functions by modulating gene expression networks. In cervical cancer cells, it competes with miR‑138 for binding sites on the hTERT 3′‑UTR, and in coordination with GRSF1, it promotes hTERT translation and simultaneously elevates AGO2 expression, thereby enhancing microRNA activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In nasopharyngeal and hepatocellular carcinomas, overexpressed miR‑346 targets tumor suppressors such as BRMS1 and KLF14 to facilitate cell migration, invasion, proliferation, and resistance to apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Its oncogenic influence is further underscored in renal cell and colorectal carcinomas, where miR‑346 modulates critical signaling pathways—the former by targeting GSK‑3β to activate Wnt/β‑catenin signaling"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", and the latter by directly repressing FBXL2 and LHX6 to promote G1‑S cell cycle transition and activate Akt/mTOR signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " In non‑small cell lung cancer and glioma, regulatory circular RNAs—circ_0069244 and circ‑TOP2A—function as sponges for miR‑346, thereby modulating downstream targets such as XPC and SUSD2 that govern cell proliferation and migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In uveal melanoma, elevated miR‑346 expression correlates with metastatic progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n \n \nBeyond its direct regulatory roles, miR‑346 also shows promise as a diagnostic and prognostic biomarker across a range of clinical conditions. Elevated serum levels of miR‑346 have been detected in patients with Mycobacterium avium complex pulmonary disease and tuberculosis, with concentrations reflecting bacterial load and therapy response."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " In autoimmune disorders such as Graves’ disease, altered miR‑346 expression in circulating CD4⁺ T cells impacts T follicular helper cell differentiation by targeting Bcl‑6 and serves as a predictor for disease relapse."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": " Aberrant miR‑346 levels in gestational tissues have been linked to adverse obstetric outcomes, and in sepsis, the MALAT1/miR‑346/SMAD3 regulatory network influences macrophage proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " Moreover, conflicting reports regarding miR‑346 expression in breast cancer underscore the complexity of its regulation and necessitate further investigation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " In addition, altered miR‑346 expression in primary sclerosing cholangitis associated with ulcerative colitis points to a putative role in modulating carcinogenic pathways in these patients."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Rafal Bartoszewski, Joseph W Brewer, Andras Rab, et al. 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