CircHIPK3 Promotes Metastasis of Gastric Cancer via miR-653-5p/miR-338-3p-NRP1 Axis Under a Long-Term Hypoxic Microenvironment
CircHIPK3 Promotes Metastasis of Gastric Cancer via miR-653-5p/miR-338-3p-NRP1 Axis Under a Long-Term Hypoxic Microenvironment
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DOI：
10.3389/fonc.2020.01612
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发表时间：
2020-08-13
影响因子：
4.7
通讯作者：
Liu, Yunpeng
中科院分区：
文献类型：
--
作者：
Jin, Yue;Che, Xiaofang;Liu, Yunpeng
作为微环境的一个重要特征，缺氧，特别是长期缺氧，已知会促进实体瘤的转移并导致预后不良。环状RNA（circRNA）参与癌症中细胞增殖和转移的重要过程。然而，在长期缺氧条件下，circRNA对转移的贡献是模糊的。本研究旨在探讨circHIPK 3在长期低氧促进胃癌转移中的特异性功能。本研究以我们建立的耐缺氧胃癌细胞系（HRGC）作为长期缺氧模型，该细胞系能耐受2%O（2）。我们发现，在HRGC细胞中，circHIPK 3被HIF-2 α上调，并且circHIPK 3促进HRGC细胞的迁移和侵袭能力。进一步研究表明，circHIPK 3通过与miR-653- 5 p和miR-338- 3 p相互作用，解除对神经纤毛蛋白1（NRP 1）的抑制，从而激活下游ERK和AKT通路，直接促进HRGC细胞的转移。我们的研究确定了circHIPK 3在长期缺氧微环境下的癌基因功能，以及使用circHIPK 3作为GC长期缺氧的潜在生物标志物的可能性。总之，在长期缺氧微环境下，circHIPK 3可通过miR-653- 5 p/miR-338- 3 p-NRP 1轴促进GC转移。
As a vital feature of the microenvironment, hypoxia, especially long-term hypoxia, is known to promote metastasis and lead to poor prognosis in solid tumors. Circular RNAs (circRNAs) participate in important processes of cell proliferation and metastasis in cancers. However, the contribution of circRNAs to metastasis under long-term hypoxia is obscure. In this study, we aim to explore specific functions of circHIPK3 in long-term hypoxia-promoting metastasis of gastric cancer (GC). The hypoxic resistant gastric cancer (HRGC) cell lines we established previously, which were tolerant to 2% O(2)conditions, were used as the long-term hypoxia model. We found that circHIPK3 was upregulated by HIF-2 alpha in HRGC cells, and circHIPK3 facilitated the migration and invasion ability of HRGC cells. Further investigation proved that circHIPK3 promoted metastasis of HRGC cells directly by interacting with miR-653-5p and miR-338-3p to relieve the suppression of neuropilin 1 (NRP1), resulting in the activation of downstream ERK and AKT pathways. Our study identified oncogene functions of circHIPK3 under a long-term hypoxic microenvironment and the possibility of using circHIPK3 as a potential biomarker of long-term hypoxia in GC. In conclusion, circHIPK3 could promote GC metastasis via the miR-653-5p/miR-338-3p-NRP1 axis under a long-term hypoxic microenvironment.