Hypoxia-induced lncRNA PDIA3P1 promotes mesenchymal transition via sponging of miR-124-3p in glioma
Hypoxia-induced lncRNA PDIA3P1 promotes mesenchymal transition via sponging of miR-124-3p in glioma
复制标题
缺氧诱导的 lncRNA PDIA3P1 通过 miR-124-3p 海绵作用促进胶质瘤中的间质转化
DOI：
10.1038/s41419-020-2345-z
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发表时间：
2020-03-03
影响因子：
9
通讯作者：
Li, Gang
中科院分区：
文献类型：
--
作者：
Wang, Shaobo;Qi, Yanhua;Li, Gang
缺氧是胶质瘤恶性进展的一个关键因素，特别是对于高侵袭性间质（MES）亚型。但缺氧诱导胶质瘤MES转化的具体机制尚不清楚。假基因，曾经被认为是进化的无功能遗物，正在成为人类肿瘤发生和发展的关键因素。本研究旨在探讨蛋白质二硫键异构酶家族A成员3假基因1（PDIA 3 P1）在缺氧诱导的胶质瘤MES转化中的临床意义、生物学功能及其机制。在本研究中，我们发现PDIA 3 P1表达与胶质瘤患者的肿瘤程度、转录组亚型和预后密切相关。富集分析发现PDIA 3 P1高表达与上皮-间质转化、细胞外基质（ECM）分解和血管生成相关。体外研究发现PDIA 3 P1的过表达增强了胶质瘤细胞的迁移和侵袭能力，而PDIA 3 P1的敲低则诱导了相反的效果。进一步的研究发现PDIA 3 P1作为ceRNA，通过海绵状吸收miR-124- 3 p来调节RELA的表达，激活下游NF-κB通路，从而促进胶质瘤细胞的MES转换。此外，缺氧诱导因子1被证实直接结合PDIA 3 P1启动子区域并激活其转录。总之，PDIA 3 P1通过PDIA 3 P1-miR-124- 3 p-RELA轴在缺氧和胶质瘤MES转变之间起关键作用，其可作为胶质瘤治疗的预后指标和潜在治疗靶点。
Hypoxia is a critical factor in the malignant progression of glioma, especially for the highly-invasive mesenchymal (MES) subtype. But the detailed mechanisms in hypoxia-induced glioma MES transition remain elusive. Pseudogenes, once considered to be non-functional relics of evolution, are emerging as a critical factor in human tumorigenesis and progression. Here, we investigated the clinical significance, biological function, and mechanisms of protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P1) in hypoxia-induced glioma MES transition. In this study, we found that PDIA3P1 expression was closely related to tumor degree, transcriptome subtype, and prognosis in glioma patients. Enrichment analysis found that high PDIA3P1 expression was associated with epithelial-mesenchymal transition, extracellular matrix (ECM) disassembly, and angiogenesis. In vitro study revealed that overexpression of PDIA3P1 enhanced the migration and invasion capacity of glioma cells, while knockdown of PDIA3P1 induced the opposite effect. Further studies revealed that PDIA3P1 functions as a ceRNA, sponging miR-124-3p to modulate RELA expression and activate the downstream NF-κB pathway, thus promoting the MES transition of glioma cells. In addition, Hypoxia Inducible Factor 1 was confirmed to directly bind to the PDIA3P1 promotor region and activate its transcription. In conclusion, PDIA3P1 is a crucial link between hypoxia and glioma MES transition through the PDIA3P1-miR-124-3p-RELA axis, which may serve as a prognostic indicator and potential therapeutic target for glioma treatment.