Hsa_circ_0058124 promotes papillary thyroid cancer tumorigenesis and invasiveness through the NOTCH3/GATAD2A axis
Hsa_circ_0058124 promotes papillary thyroid cancer tumorigenesis and invasiveness through the NOTCH3/GATAD2A axis
复制标题
Hsa_circ_0058124通过NOTCH3/GATAD2A轴促进乳头状甲状腺癌肿瘤发生和侵袭
DOI：
10.1186/s13046-019-1321-x
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发表时间：
2019-07-19
影响因子：
11.3
通讯作者：
Zhang, Yuan
中科院分区：
文献类型：
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作者：
Yao, Yao;Chen, Xinyuan;Zhang, Yuan
背景甲状腺乳头状癌（papillary thyroid cancer，PTC）虽然总体预后良好，但由于其侵袭性和转移性，仍会影响许多患者的生活质量，甚至危及生命。新兴的研究表明，环状RNA（circRNA）参与各种癌症的调控。然而，在浸润性PTC的circRNA的配置文件仍然没有很好地understood.MethodsCompeting内源性RNA（ceRNA）微阵列进行，以确定circRNA有助于PTC的肿瘤发生和侵袭性。使用生物信息学方法来缩小候选circRNA。定量实时聚合酶链反应（qRT-PCR）分析显示PTC组织中hsa_circ_0058124的显著上调，与PTC患者的不良预后密切相关。采用RNA荧光原位杂交和细胞分级分离技术对hsa_circ_0058124进行亚细胞定位。通过细胞增殖、细胞周期、细胞凋亡、迁移和侵袭实验，检测hsa_circ_0058124在PTC中的作用。在机制上，应用RNA测序和GSEA分析来预测hsa_circ_0058124的下游途径。使用双荧光素酶报告测定来探索hsa_circ_0058124的潜在miRNA海绵作用。采用蛋白质印迹、细胞增殖、细胞周期、细胞凋亡、迁移和侵袭以及小鼠异种移植试验来验证hsa_circ_0058124/NOTCH 3/GATAD 2A轴对PTC进展的影响。结果在本研究中，在PTC中发现并探索了2 q35上的新hsa_circ_0058124。Hsa_circ_0058124与PTC患者的恶性特征和不良结局相关。Hsa_circ_0058124作为致癌驱动因子，促进PTC细胞增殖、致瘤性、肿瘤侵袭和转移，其作为竞争性内源性RNA调节miRNA-218- 5 p及其靶基因NUMB表达，结论本研究揭示了一种新的生物标志物面板组成的hsa_circ_0058124/N 0 TCH 3/GATAD 2A轴，其对于PTC肿瘤发生和侵袭性是关键的，并且可能代表用于干预PTC进展的新的治疗靶点。
BackgroundDespite a good and overall prognosis, papillary thyroid cancer (PTC) can still affect the quality of life of many patients, and can even be life-threatening due to its invasiveness and metastasis. Emerging studies demonstrate that circular RNAs (circRNAs) participate in the regulation of various cancers. However, the circRNA profile in invasive PTC is still not well understood.MethodsCompeting endogenous RNA (ceRNA) microarrays were performed to determine circRNAs contributed to the tumorigenesis and invasiveness of PTC. Bioinformatics methods were used to narrow down the candidate circRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) assays revealed a significant upregulation of hsa_circ_0058124 in PTC tissue and a close correlation with a poor prognosis for PTC patients. RNA fluorescence in situ hybridization and Cell fractionation assay were used to investigate the subcellular location of hsa_circ_0058124. Then, we examined the functions of hsa_circ_0058124 in PTC by cell proliferation, cell cycle, apoptosis, migration and invasion assay. Mechanistically, RNA sequencing and GSEA analysis were applied to predict the downstream pathway of hsa_circ_0058124. Dual-luciferase report assays were used to explore the potential miRNA sponge role of hsa_circ_0058124. Western blotting, cell proliferation, cell cycle, cell apoptosis, migration and invasion, and mouse xenograft assay were used to validate the effects of hsa_circ_0058124/NOTCH3/GATAD2A axis on PTC progression.ResultsIn the current study, a novel hsa_circ_0058124 on 2q35 was identified and explored in PTC. Hsa_circ_0058124 is associated with the malignant features and poor outcomes of PTC patients. Hsa_circ_0058124 acts as an oncogenic driver that promotes PTC cell proliferation, tumorigenicity, tumor invasion, and metastasis, which functions as a competing endogenous RNA to modulate miRNA-218-5p and its target gene NUMB expression, and consequently with repression of the NOTCH3/GATAD2A signaling axis in vitro and in vivo.ConclusionsThis study unveils a novel biomarker panel consisting of the hsa_circ_0058124/NOTCH3/GATAD2A axis which is critical for PTC tumorigenesis and invasiveness and may represent a novel therapeutic target for intervening in PTC progression.