{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Long non‐coding RNA FOXD3‑AS1 has emerged as a versatile regulator in human disease, with its function appearing to be highly context‐dependent. In several malignancies—including cutaneous melanoma, colorectal cancer, lung cancer, nasopharyngeal carcinoma, cervical cancer, glioblastoma, and breast cancer—FOXD3‑AS1 is frequently overexpressed and promotes oncogenic processes such as cell proliferation, migration, invasion, and chemoresistance. Mechanistically, FOXD3‑AS1 commonly acts as a competing endogenous RNA (ceRNA) that sponges distinct microRNAs (for example, miR‑325, miR‑135a‑5p, miR‑128‑3p, miR‑296‑5p, miR‑127‑3p, and miR‑185‑3p) to regulate downstream effectors including MAP3K2, SIRT1, ELAVL1/PI3K–Akt, TGF‑β1/Smads, MED28, CDK6, WEE1, and FOXD3 itself."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In contrast, in certain contexts such as a subset of non‑small cell lung cancers and neuroblastoma, FOXD3‑AS1 expression is reduced and its restoration has been linked to tumor‐suppressive effects, with evidence of inhibited proliferation and invasion following FOXD3‑AS1 upregulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond oncogenesis, FOXD3‑AS1 has also been implicated in non-malignant pathophysiological conditions. For example, in myocardial ischemia/reperfusion injury and cerebral ischemia/reperfusion, increased FOXD3‑AS1 expression exacerbates tissue damage by promoting autophagy, apoptosis, and inflammatory signaling via activation of pathways such as NF‑κB."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In glioma, elevated FOXD3‑AS1 correlates positively with FOXD3 mRNA levels and is associated with high-grade tumors and poor prognosis, further underscoring its oncogenic potential."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, FOXD3‑AS1 has been shown to modulate chemoresistance in cisplatin‐resistant non‑small cell lung cancer by sponging miR‑127‑3p to upregulate MDM2, while its regulation of CDK6 via miR‑135a‑5p has also been described in lung cancer models."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, recent functional screening in differentiating human embryonic stem cells has identified FOXD3‑AS1 as an essential regulator of pluripotency and lineage commitment, suggesting that its roles extend into early developmental processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies highlight that FOXD3‑AS1 can function as either an oncogene or tumor suppressor—and as a modulator of stress responses—depending on the cellular context. Its diverse mechanisms, which include acting as a ceRNA to regulate key signaling cascades, render FOXD3‑AS1 a promising prognostic biomarker and a potential therapeutic target in a spectrum of diseases.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xige Chen, Juan Gao, Yanhua Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LncRNA FOXD3-AS1 promotes proliferation, invasion and migration of cutaneous malignant melanoma via regulating miR-325/MAP3K2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Pharmacother (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biopha.2019.109438"}], "href": "https://doi.org/10.1016/j.biopha.2019.109438"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31541886"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31541886"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Qiong Wu, Min Shi, Wenying Meng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Long noncoding RNA FOXD3-AS1 promotes colon adenocarcinoma progression and functions as a competing endogenous RNA to regulate SIRT1 by sponging miR-135a-5p."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Physiol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcp.28752"}], "href": "https://doi.org/10.1002/jcp.28752"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31058315"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31058315"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Guangxian Mao, Zhimin Mu, D A Wu "}, {"type": "b", "children": [{"type": "t", "text": "Exosomal lncRNA FOXD3-AS1 upregulates ELAVL1 expression and activates PI3K/Akt pathway to enhance lung cancer cell proliferation, invasion, and 5-fluorouracil resistance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Biochim Biophys Sin (Shanghai) (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/abbs/gmab129"}], "href": "https://doi.org/10.1093/abbs/gmab129"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34605863"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34605863"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yonghui Chen, Hongbo Gao, Yaomei Li "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of LncRNA FOXD3-AS1 suppresses the aggressive biological behaviors of thyroid cancer via elevating miR-296-5p and inactivating TGF-β1/Smads signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Endocrinol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mce.2019.110634"}], "href": "https://doi.org/10.1016/j.mce.2019.110634"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31678422"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31678422"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Yi Lu, Yao Han, Jinlin He, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LncRNA FOXD3-AS1 knockdown protects against cerebral ischemia/reperfusion injury via miR-765/BCL2L13 axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Pharmacother (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biopha.2020.110778"}], "href": "https://doi.org/10.1016/j.biopha.2020.110778"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33068927"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33068927"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yaoyao Guan, Adheesh Bhandari, Erjie Xia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "lncRNA FOXD3-AS1 is associated with clinical progression and regulates cell migration and invasion in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Biochem Funct (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cbf.3393"}], "href": "https://doi.org/10.1002/cbf.3393"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31017311"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31017311"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Xiufang Yang, Huilan Du, Wenhui Bian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FOXD3‑AS1/miR‑128‑3p/LIMK1 axis regulates cervical cancer progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.2021.8013"}], "href": "https://doi.org/10.3892/or.2021.8013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33760158"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33760158"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Z-L Zeng, H-K Zhu, L-F He, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Highly expressed lncRNA FOXD3-AS1 promotes non-small cell lung cancer progression via regulating miR-127-3p/mediator complex subunit 28 axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Rev Med Pharmacol Sci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.26355/eurrev_202003_20520"}], "href": "https://doi.org/10.26355/eurrev_202003_20520"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32196603"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32196603"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Tao Ji, Yanan Zhang, Zheng Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FOXD3-AS1 suppresses the progression of non-small cell lung cancer by regulating miR-150/SRCIN1axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biomark (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3233/CBM-200059"}], "href": "https://doi.org/10.3233/CBM-200059"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32924985"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32924985"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Zaisheng Ling, Jinpeng Zhang, Qingqing Liu "}, {"type": "b", "children": [{"type": "t", "text": "Oncogenic Forkhead box D3 antisense RNA 1 promotes cell survival and confers temozolomide resistance in glioblastoma cells through the miR-128-3p/WEE1 G2 checkpoint kinase axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Bioengineered (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/21655979.2022.2042133"}], "href": "https://doi.org/10.1080/21655979.2022.2042133"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35191808"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35191808"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jiang Hu, Jun Pan, Zhiguo Luo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Long non-coding RNA FOXD3-AS1 silencing exerts tumor suppressive effects in nasopharyngeal carcinoma by downregulating FOXD3 expression via microRNA-185-3p upregulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Gene Ther (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41417-020-00242-z"}], "href": "https://doi.org/10.1038/s41417-020-00242-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33204001"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33204001"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Guoxin Tong, Yongmei Wang, Chenke Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Long non-coding RNA FOXD3-AS1 aggravates ischemia/reperfusion injury of cardiomyocytes through promoting autophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Transl Res (2019)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31632535"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31632535"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Xiang Zhao, Dan Li, Dandan Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Retracted: Risk-Associated Long Noncoding RNA FOXD3-AS1 Inhibits Neuroblastoma Progression by Repressing PARP1-Mediated Activation of CTCF."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Ther (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymthe.2017.12.017"}], "href": "https://doi.org/10.1016/j.ymthe.2017.12.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29398485"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29398485"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Zhaolong Zeng, Guofang Zhao, Huangkai Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LncRNA FOXD3-AS1 promoted chemo-resistance of NSCLC cells via directly acting on miR-127-3p/MDM2 axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell Int (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12935-020-01402-9"}], "href": "https://doi.org/10.1186/s12935-020-01402-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32742197"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32742197"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Jiayong Zheng, Bangtian Peng, Yanwei Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FOXD3-AS1 Knockdown Suppresses Hypoxia-Induced Cardiomyocyte Injury by Increasing Cell Survival and Inhibiting Apoptosis "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "via"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Upregulating Cardioprotective Molecule miR-150-5p "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "In Vitro"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": "."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Pharmacol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fphar.2020.01284"}], "href": "https://doi.org/10.3389/fphar.2020.01284"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32973515"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32973515"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Jeffrey R Haswell, Kaia Mattioli, Chiara Gerhardinger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide CRISPR interference screen identifies long non-coding RNA loci required for differentiation and pluripotency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0252848"}], "href": "https://doi.org/10.1371/journal.pone.0252848"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34731163"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34731163"}]}]}]}