{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nmiR-558 acts as a critical regulator of gene expression in various cancers by binding directly to regulatory regions to enhance the transcription or translation of pro‐oncogenic targets. For instance, in neuroblastoma, miR-558 binds to a specific promoter region of the heparanase (HPSE) gene to upregulate its transcription and also promotes the translation of hypoxia-inducible factor-2α (HIF-2α) through interactions that recruit Argonaute proteins. In gastric cancer, miR-558 similarly overcomes Smad4-mediated repression to increase HPSE expression. Moreover, in bladder cancer, reduced levels of a circular RNA (circHIPK3) diminish its ability to sponge miR-558, thereby enhancing miR-558’s capacity to induce HPSE expression and drive tumor aggressiveness."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn lung cancer, miR-558 contributes to treatment resistance and malignant progression through a dual mechanism. On one hand, it targets apoptosis-associated tyrosine kinase (AATK), thereby diminishing apoptotic responses and increasing cell survival following ionizing radiation. On the other hand, another circular RNA (hsa_circ_0030998) functions as a molecular sponge to sequester miR-558, and its downregulation correlates with enhanced tumor cell proliferation, migration, and invasion. These findings underscore miR-558’s role in modulating both inherent oncogenic signaling and the cellular response to radiotherapy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond oncogenesis, miR-558 is involved in the pathogenesis of non-malignant conditions. In osteoarthritis, it has been implicated in the interleukin-1β-mediated induction of cyclooxygenase-2 (COX-2), suggesting a role in inflammatory processes. In the context of preeclampsia, several competing endogenous RNAs—including lncRNA Linc00261, circ-OPHN1, and circ_0043610—sequester miR-558, which in turn modulates targets such as TIMP4 and RYBP, thereby affecting trophoblast cell invasion, migration, and apoptosis. Additionally, a regulatory axis involving miR-558 and TNFRSF1A has been suggested to influence the progression of chronic obstructive pulmonary disease, further highlighting the diverse physiological roles of miR-558."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hongxia Qu, Liduan Zheng, Jiarui Pu, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "microRNA-558 facilitates the expression of hypoxia-inducible factor 2 alpha through binding to 5'-untranslated region in neuroblastoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.9813"}], "href": "https://doi.org/10.18632/oncotarget.9813"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27276678"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27276678"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Liduan Zheng, Wanju Jiao, Huajie Song, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "CircHIPK3 sponges miR-558 to suppress heparanase expression in bladder cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embr.201643581"}], "href": "https://doi.org/10.15252/embr.201643581"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28794202"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28794202"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Rui-Xia Zhu, Chun-Hui Song, Jin-Shan Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Downregulation of AATK mediates microRNA-558-induced resistance of A549 cells to radiotherapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/mmr.2016.5579"}], "href": "https://doi.org/10.3892/mmr.2016.5579"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27485693"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27485693"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Xiaoping Li, Yiling Feng, Bo Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel circular RNA, hsa_circ_0030998 suppresses lung cancer tumorigenesis and Taxol resistance by sponging miR-558."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Oncol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/1878-0261.12852"}], "href": "https://doi.org/10.1002/1878-0261.12852"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33190405"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33190405"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "S J Park, E J Cheon, H A Kim "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-558 regulates the expression of cyclooxygenase-2 and IL-1β-induced catabolic effects in human articular chondrocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Osteoarthritis Cartilage (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.joca.2013.04.012"}], "href": "https://doi.org/10.1016/j.joca.2013.04.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23611898"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23611898"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Dan Cheng, Shan Jiang, Jiao Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Upregulated long noncoding RNA Linc00261 in pre-eclampsia and its effect on trophoblast invasion and migration via regulating miR-558/TIMP4 signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biochem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcb.28598"}], "href": "https://doi.org/10.1002/jcb.28598"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30891826"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30891826"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Xubo Jing, Zhaoji Luan, Baoliang Liu "}, {"type": "b", "children": [{"type": "t", "text": "miR-558 Reduces the Damage of HBE Cells Exposed to Cigarette Smoke Extract by Targeting TNFRSF1A and Inactivating TAK1/MAPK/NF-κB Pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunol Invest (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/08820139.2021.1874977"}], "href": "https://doi.org/10.1080/08820139.2021.1874977"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33459100"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33459100"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Yu Li, Jinzao Chen, Shuqin Song "}, {"type": "b", "children": [{"type": "t", "text": "Circ-OPHN1 suppresses the proliferation, migration, and invasion of trophoblast cells through mediating miR-558/THBS2 axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Drug Dev Res (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ddr.21931"}], "href": "https://doi.org/10.1002/ddr.21931"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35277867"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35277867"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jing Shang, Li Lin, Xiumin Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Re-expression of circ_0043610 contributes to trophoblast dysfunction through the miR-558/RYBP pathway in preeclampsia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocr J (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1507/endocrj.EJ22-0153"}], "href": "https://doi.org/10.1507/endocrj.EJ22-0153"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35908953"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35908953"}]}]}]}