{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMiR‐515, predominantly the 5p species (and in one report the 3p isoform), has emerged as a critical tumor‐suppressive microRNA in several cancer types. In breast, lung, and liver cancers, its expression is frequently down‐regulated, thereby relieving repression of key oncogenic mediators. For instance, miR‐515‐5p directly targets MARK4 to inhibit cancer cell migration and metastasis, while it also counteracts estrogen‐driven proliferation in breast cancer by repressing sphingosine kinase 1 (SK1) activity. Moreover, in non‐small cell lung cancer (NSCLC), miR‐515‐5p reduces cell survival and metastasis through direct targeting of chemokine CXCL6, and in hepatocellular carcinoma its overexpression impairs the IL‐6/JAK/STAT3 cascade to inhibit invasion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "Disruptions in miR‐515 regulation can occur not only at the transcriptional level but also through competitive endogenous RNA mechanisms and genetic variations. A single nucleotide polymorphism in the 3′‐UTR of IGF‐1R that interferes with miR‐515‐5p binding has been associated with increased IGF‐1R levels and modified breast cancer risk in BRCA1 mutation carriers. Moreover, several oncogenic circular RNAs (circRNAs) and long non‐coding RNAs (lncRNAs) have been shown to “sponge” miR‐515‐5p in various malignancies including gastric, prostate, oral squamous cell, and cutaneous squamous cell carcinomas. These sponging events relieve miR‐515‐mediated suppression of downstream targets such as XIAP, TGF‐β1, FKBP1A, TPX2, and SLIT3. In addition, separate investigations into gastric cancer have examined the related miR‐515‐3p, reinforcing the concept that disruption of miR‐515 activity contributes to tumor progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "12"}]}, {"type": "t", "text": "Beyond its anticancer functions, miR‐515‐5p contributes to the regulation of cell cycle progression and non‐tumorigenic pathophysiological processes. For example, in colorectal cancer, exogenous miR‐515‐5p induces G1 phase arrest and promotes apoptosis by targeting MAD2L1. In noncancer settings, elevated circulating miR‐515‐5p in maternal serum appears to impair trophoblast proliferation and invasion by suppressing XIAP, while in osteoarthritis models its overexpression attenuates chondrocyte apoptosis and the inflammatory response."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "15"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Filipa G Pinho, Adam E Frampton, Joao Nunes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Downregulation of microRNA-515-5p by the estrogen receptor modulates sphingosine kinase 1 and breast cancer cell proliferation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-13-0158"}], "href": "https://doi.org/10.1158/0008-5472.CAN-13-0158"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23928990"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23928990"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Olivier E Pardo, Leandro Castellano, Catriona E Munro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-515-5p controls cancer cell migration through MARK4 regulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embr.201540970"}], "href": "https://doi.org/10.15252/embr.201540970"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26882547"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26882547"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jun Li, Zhiyuan Tang, Haiying Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CXCL6 promotes non-small cell lung cancer cell survival and metastasis via down-regulation of miR-515-5p."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Pharmacother (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biopha.2017.11.004"}], "href": "https://doi.org/10.1016/j.biopha.2017.11.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29136957"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29136957"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jun-Sheng Ni, Hao Zheng, Yang-Liu Ou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-515-5p suppresses HCC migration and invasion via targeting IL6/JAK/STAT3 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Surg Oncol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.suronc.2020.03.003"}], "href": "https://doi.org/10.1016/j.suronc.2020.03.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32891315"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32891315"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Avital Gilam, Liat Edry, Efrat Mamluk-Morag, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of IGF-1R regulation by miR-515-5p modifies breast cancer risk among BRCA1 carriers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Breast Cancer Res Treat (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10549-013-2502-5"}], "href": "https://doi.org/10.1007/s10549-013-2502-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23549953"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23549953"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Haibo Zhang, Xiumin Wang, Hongchun Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hsa_circ_0067997 promotes the progression of gastric cancer by inhibition of miR-515-5p and activation of X chromosome-linked inhibitor of apoptosis (XIAP)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Artif Cells Nanomed Biotechnol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/21691401.2018.1553787"}], "href": "https://doi.org/10.1080/21691401.2018.1553787"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30688097"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30688097"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Xue Han, Xing Li, Hengyu Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serum miR-515-3p, a potential new RNA biomarker, is involved in gastric carcinoma."}]}, {"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.28854"}], "href": "https://doi.org/10.1002/jcb.28854"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31081157"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31081157"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Guangwen Wang, Haiyang Zhao, Xiaohong Duan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CircRNA pappalysin 1 facilitates prostate cancer development through miR-515-5p/FKBP1A axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Andrologia (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/and.14227"}], "href": "https://doi.org/10.1111/and.14227"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34469009"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34469009"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Jiawei Yan, Hongyan Xu "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of transforming growth factor-beta1 by circANKS1B/miR-515-5p affects the metastatic potential and cisplatin resistance in oral squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Bioengineered (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/21655979.2021.2005221"}], "href": "https://doi.org/10.1080/21655979.2021.2005221"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34781814"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34781814"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Lipeng Wang, Shaozhang Hou, Jianning Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Circular RNA circ-LARP1B contributes to cutaneous squamous cell carcinoma progression by targeting microRNA-515-5p/TPX2 microtubule nucleation factor axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Bioengineered (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/21655979.2021.2019172"}], "href": "https://doi.org/10.1080/21655979.2021.2019172"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34982022"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34982022"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Yu Tang, Jingxuan Cai, Bo Lv "}, {"type": "b", "children": [{"type": "t", "text": "LncRNA ubiquitin-binding protein domain protein 10 antisense RNA 1 inhibits colon adenocarcinoma progression via the miR-515-5p/slit guidance ligand 3 axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Bioengineered (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/21655979.2021.2024396"}], "href": "https://doi.org/10.1080/21655979.2021.2024396"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35034539"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35034539"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Xiao-Min Ran, Juan Yang, Zi-Yi Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "M2 macrophage-derived exosomal circTMCO3 acts through miR-515-5p and ITGA8 to enhance malignancy in ovarian cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Commun Biol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s42003-024-06095-8"}], "href": "https://doi.org/10.1038/s42003-024-06095-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38755265"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38755265"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Xiang Ding, Qingyan Fu, Weixing Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeting of MAD2L1 by miR-515-5p involves the regulation of cell cycle arrest and apoptosis of colorectal cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Biol Int (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cbin.11774"}], "href": "https://doi.org/10.1002/cbin.11774"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35143103"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35143103"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Misa Nunode, Masami Hayashi, Yoko Nagayasu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-515-5p suppresses trophoblast cell invasion and proliferation through XIAP regulation in preeclampsia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Endocrinol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mce.2022.111779"}], "href": "https://doi.org/10.1016/j.mce.2022.111779"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36155776"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36155776"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Dongfeng Cai, Zixiao Yang, Chao Zhong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[miR-515-5p targeting Toll-like receptor 4 regulates myeloid differentiation primary response gene 88/nuclear factor-kappa B pathway to inhibit apoptosis and inflammatory response of osteoarthritis chondrocytes]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7507/1002-1892.202312091"}], "href": "https://doi.org/10.7507/1002-1892.202312091"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38500425"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38500425"}]}]}]}