Department of Head and Neck Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China.
Department of Immunology, Key Laboratory of Immune Microenvironment and Disease, Nanjing Medical University, Nanjing, 211166, China.
J Exp Clin Cancer Res. 2019 Jul 19;38(1):318. doi: 10.1186/s13046-019-1321-x.
Despite 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.
Competing 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.
In 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.
This 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.
尽管甲状腺乳头状癌（PTC）总体预后良好，但仍会影响许多患者的生活质量，甚至因其侵袭性和转移性而危及生命。新兴研究表明，环状 RNA（circRNA）参与了多种癌症的调控。然而，浸润性 PTC 的 circRNA 谱仍未得到很好的理解。
竞争性内源性 RNA（ceRNA）微阵列用于确定 circRNAs 对 PTC 发生和侵袭的贡献。生物信息学方法用于缩小候选 circRNAs 的范围。实时定量聚合酶链反应（qRT-PCR）检测显示 hsa_circ_0058124 在 PTC 组织中显著上调，并与 PTC 患者预后不良密切相关。RNA 荧光原位杂交和细胞分馏实验用于研究 hsa_circ_0058124 的亚细胞定位。然后，通过细胞增殖、细胞周期、凋亡、迁移和侵袭实验检测 hsa_circ_0058124 在 PTC 中的功能。机制上，应用 RNA 测序和 GSEA 分析预测 hsa_circ_0058124 的下游通路。双荧光素酶报告实验用于探索 hsa_circ_0058124 的潜在 miRNA 海绵作用。Western blot、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实验用于验证 hsa_circ_0058124/NOTCH3/GATAD2A 轴对 PTC 进展的影响。
本研究鉴定并研究了 2q35 上的一种新型 hsa_circ_0058124 在 PTC 中的作用。hsa_circ_0058124 与 PTC 患者的恶性特征和不良预后相关。hsa_circ_0058124 作为一种致癌驱动因子，促进 PTC 细胞增殖、肿瘤发生、肿瘤侵袭和转移，作为竞争性内源性 RNA 调节 miRNA-218-5p 及其靶基因 NUMB 的表达，并由此抑制 NOTCH3/GATAD2A 信号通路的体外和体内。
本研究揭示了一个由 hsa_circ_0058124/NOTCH3/GATAD2A 轴组成的新型生物标志物谱，该标志物谱对 PTC 的发生和侵袭至关重要，可能代表干预 PTC 进展的新治疗靶点。
