{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nmiR-596 has emerged as a potent tumor‐suppressive microRNA in several malignancies. In oral squamous cell carcinoma (OSCC), miR-596 is frequently silenced by promoter hypermethylation, leading to the overexpression of its direct target LGALS3BP. Restoration of miR-596 not only suppresses LGALS3BP levels but also results in reduced ERK1/2 phosphorylation, thereby inhibiting cell growth and triggering apoptosis. These findings underscore its potential as a candidate for miRNA replacement anticancer therapy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in OSCC, miR-596 has been shown to function as a key inducer of apoptosis in mammalian cells via p53 regulation. By directly targeting the E3 ligase Smurf1, miR-596 indirectly stabilizes p53—normally attenuated by MDM2—ultimately promoting apoptotic cell death. This mechanism contributes to reduced cell migration and proliferation, which correlates with improved overall survival in cancer patients."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn melanoma, overexpression of miR-596 significantly inhibits the MAPK/ERK signaling pathway through direct targeting of MEK1, as well as anti-apoptotic proteins MCL1 and BCL2L1. These actions not only curb cell proliferation, migration, and invasion but also enhance apoptotic rates, demonstrating its critical value as both a prognostic factor and a therapeutic candidate in melanoma management."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSimilarly, in gastric cancer, miR-596 acts as a tumor suppressor by regulating the expression of peroxiredoxin 1 (PRDX1). Its downregulation—often linked to increased promoter methylation—is associated with gastric tumorigenesis, suggesting that restoring miR-596 levels may counteract cancer progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence also points to a potential diagnostic role for miR-596 in non-traumatic osteonecrosis of the femoral head, although the precise mechanisms by which it operates in this condition remain to be elucidated."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn prostatic cancer, while the detailed biological mechanisms of miR-596 remain under investigation, preliminary studies indicate that it may play a tumor-suppressive role similar to that observed in other cancer types, representing a promising avenue for future research."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, in the context of gastric cancer, recent studies have unveiled a novel regulatory axis in which exosomal circPRRX1 functions as a competing endogenous RNA that sequesters miR-596. This sponging effect modulates the expression of NF-κB activating protein (NKAP), thereby influencing tumorigenesis and cellular sensitivity to radiation therapy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn glioma, miR-596 directly targets oncogenic factors such as CREPT, leading to the attenuation of Wnt/β-catenin signaling. This results in reduced cellular proliferation and invasion, further establishing miR-596 as a key negative regulator of tumor progression across multiple cancer types."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hironori Endo, Tomoki Muramatsu, Mayuko Furuta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Potential of tumor-suppressive miR-596 targeting LGALS3BP as a therapeutic agent in oral cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgs376"}], "href": "https://doi.org/10.1093/carcin/bgs376"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23233740"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23233740"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Hui Li "}, {"type": "b", "children": [{"type": "t", "text": "Exploration of Alternative Mechanism for MiR-596-mediated Down-regulation of LGALS3BP in Oral Squamous Cell Carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Kokubyo Gakkai Zasshi (2015)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26502662"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26502662"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Ming Ma, Junyu Yang, Bolun Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High-Throughput Identification of miR-596 Inducing p53-Mediated Apoptosis in HeLa and HCT116 Cells Using Cell Microarray."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "SLAS Technol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/2472630317720870"}], "href": "https://doi.org/10.1177/2472630317720870"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28732184"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28732184"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Szu-Mam Liu, Chen-Huan Lin, Jean Lu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-596 Modulates Melanoma Growth by Regulating Cell Survival and Death."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jid.2017.11.016"}], "href": "https://doi.org/10.1016/j.jid.2017.11.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29183729"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29183729"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Zhen Zhang, Dong-Qiu Dai "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-596 acts as a tumor suppressor in gastric cancer and is upregulated by promotor demethylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "World J Gastroenterol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3748/wjg.v25.i10.1224"}], "href": "https://doi.org/10.3748/wjg.v25.i10.1224"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30886505"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30886505"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ligong Fu, Huawei Liu, Weijun Lei "}, {"type": "b", "children": [{"type": "t", "text": "MiR-596 inhibits osteoblastic differentiation and cell proliferation by targeting Smad3 in steroid-induced osteonecrosis of femoral head."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Orthop Surg Res (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13018-020-01688-5"}], "href": "https://doi.org/10.1186/s13018-020-01688-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32410637"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32410637"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "J Dai, G Yuan, Y Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-596 is epigenetically inactivated and suppresses prostatic cancer cell growth and migration via regulating Wnt/β-catenin signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Transl Oncol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12094-020-02536-y"}], "href": "https://doi.org/10.1007/s12094-020-02536-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33387246"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33387246"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Yuxin He, Liangjian Zheng, Mengzhen Yuan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Exosomal circPRRX1 functions as a ceRNA for miR-596 to promote the proliferation, migration, invasion, and reduce radiation sensitivity of gastric cancer cells via the upregulation of NF-κB activating protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Anticancer Drugs (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/CAD.0000000000001358"}], "href": "https://doi.org/10.1097/CAD.0000000000001358"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36206097"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36206097"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Minghao Wei, Yidong Cao, Dong Jia, et al. 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