A novel hypoxia-stimulated lncRNA HIF1A-AS3 binds with YBX1 to promote ovarian cancer tumorigenesis by suppressing p21 and AJAP1 transcription
A novel hypoxia-stimulated lncRNA HIF1A-AS3 binds with YBX1 to promote ovarian cancer tumorigenesis by suppressing p21 and AJAP1 transcription
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DOI：
10.1002/mc.23620
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发表时间：
2023-08-17
影响因子：
4.6
通讯作者：
Wang，Changyu
中科院分区：
文献类型：
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作者：
Xie，Wan;Wang，Weijiao;Wang，Changyu
缺氧是卵巢肿瘤（OC）微环境的特征，并深刻影响肿瘤发生和治疗反应。长链非编码RNA（lncRNA）在肿瘤进展中发挥着各种作用;然而，lncRNA在OC微环境病理反应中的特征尚未完全了解。通过高通量测序，探索并分析了缺氧（1%O2）和常氧（21%O2）SKOV 3细胞中的lncRNA表达。利用互补DNA末端的5′-和3′-快速扩增来检测新的HIF 1A-AS 3转录物的全长。采用真实的实时定量聚合酶链反应评估OC细胞和组织中HIF 1A-AS 3的表达。进行缺氧HIF 1A-AS 3的生物学功能的体外和体内评价。为了阐明HIF 1A-AS 3在缺氧OC中的潜在机制，使用了双荧光素酶测定、染色质免疫沉淀、RNA下拉、RNA免疫沉淀和RNA测序。我们使用高通量测序来研究一种新的lncRNA，HIF 1A-AS 3，作为OC细胞/组织中显著升高的缺氧候选物。HIF 1A-AS 3主要定位于细胞核中，并促进体外和体内OC生长和肿瘤发生。缺氧诱导因子1α与HIF 1A-AS 3启动子区域的缺氧反应元件结合，并刺激其在缺氧中的表达。在缺氧条件下，HIF 1A-AS 3直接与Y-Box结合蛋白1整合，并抑制其与p21和AJAP 1启动子结合的能力，从而抑制其转录活性，从而促进缺氧OC进展。我们的研究结果揭示了新的缺氧HIF 1A-AS 3在OC肿瘤发生中的关键作用和机制。新的HIF 1A-AS 3可能是未来OC治疗的关键生物标志物和治疗靶点。
Hypoxia is characteristic of the ovarian tumor (OC) microenvironment and profoundly affects tumorigenesis and therapeutic response. Long noncoding RNAs (lncRNAs) play various roles in tumor progression; however, the characteristics of lncRNAs in pathological responses of the OC microenvironment are not entirely understood. Through high‐throughput sequencing, lncRNA expression in hypoxia (1% O2) and normoxia (21% O2) SKOV3 cells was explored and analyzed. The 5′‐ and 3′‐rapid amplification of complementary DNA ends was used to detect the full length of the novel HIF1A‐AS3 transcript. Real‐time quantitative polymerase chain reaction was used to assess HIF1A‐AS3 expression in OC cells and tissues. In vitro and in vivo evaluations of the biological functions of hypoxic HIF1A‐AS3 were conducted. To clarify the underlying mechanisms of HIF1A‐AS3 in hypoxic OC, a dual‐luciferase assay, chromatin immunoprecipitation, RNA pull‐down, RNA immunoprecipitation, and RNA‐sequencing were used. We used high‐throughput sequencing to investigate a novel lncRNA, HIF1A‐AS3, as a hypoxic candidate significantly elevated in OC cells/tissues. HIF1A‐AS3 was predominantly localized in the nucleus and promoted in vitro and in vivo OC growth and tumorigenesis. Hypoxia‐inducible factor 1α bound to hypoxia response elements in the HIF1A‐AS3 promoter region and stimulated its expression in hypoxia. Under hypoxia, HIF1A‐AS3 directly integrated with Y‐Box binding protein 1 and inhibited its ability to bind to the promoters of p21 and AJAP1 to repress their transcriptional activity, thereby promoting hypoxic OC progression. Our results revealed the crucial role and mechanism of the novel hypoxic HIF1A‐AS3 in the oncogenesis of OC. The novel HIF1A‐AS3 could be a crucial biomarker and therapeutic target for future OC treatments.