Circular RNA circPIP5K1A promotes non-small cell lung cancer proliferation and metastasis through miR-600/HIF-1α regulation
Circular RNA circPIP5K1A promotes non-small cell lung cancer proliferation and metastasis through miR-600/HIF-1α regulation
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DOI：
10.1002/jcb.29225
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发表时间：
2019-11-01
影响因子：
4
通讯作者：
Zhang, Denghai
中科院分区：
文献类型：
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作者：
Chi, Yongbing;Luo, Qiancheng;Zhang, Denghai
环状RNA（circRNA）在人类疾病中具有重要的功能，特别是在癌症中。circRNA hsa_circ_0014130（circPIP 5 K1 A）是一种特别丰富的circRNA，参与非小细胞肺癌（NSCLC）的肿瘤发生，尽管其潜在的调节机制仍不清楚。在这里，我们研究了circPIP 5 K1 A在NSCLC中的作用。实时荧光定量PCR检测circPIP 5 K1 A在NSCLC细胞系中的表达。通过circPIP 5 K1 A沉默、miR-600模拟转染和低氧诱导因子（HIF）-1 α过表达，评估circPIP 5 K1 A对NSCLC的影响，然后评估裸鼠中的细胞增殖、转移和肿瘤发生。通过荧光原位杂交（FISH）评估circPIP 5 K1 A的亚细胞定位，并通过荧光素酶测定评估circPIP 5 K1 A、miR-600和HIF-1 α之间的相关性。数据表明，circPIP 5 K1 A表达在NSCLC细胞中增加。FISH显示circPIP 5 K1 A定位于细胞质。circPIP 5 K1 A敲低通过促进miR-600的表达来抑制NSCLC细胞的转移和增殖。miR-600过表达可通过下调内皮间质转化相关蛋白Snail和vimentin，上调E-cadherin，抑制HIF-1 α介导的NSCLC细胞转移和增殖。体内实验表明，circPIP 5 K1 A沉默抑制肿瘤生长和肺转移。circPIP 5 K1 A可能作为miR-600海绵，通过促进HIF-1 α促进NSCLC增殖和转移。双荧光素报告子实验证实miR-600是circPIP 5 K1 A靶标，并且miR-600与HIF-1 α的3 '非翻译区相互作用。这些结果表明，circPIP 5 K1 A通过新的circPIP 5 K1 A/miR-600/HIF-1 α轴作为肿瘤促进剂，这为NSCLC提供了候选标志物和治疗靶点。
Circular RNAs (circRNAs) have an important function in human diseases, especially in cancer. circRNA hsa_circ_0014130 (circPIP5K1A), a particularly abundant circRNA, participates in the tumorigenesis of non-small cell lung cancer (NSCLC), although the underlying regulatory mechanism remains unclear. Here, we investigated the circPIP5K1A role in NSCLC. Expression of circPIP5K1A in NSCLC cell lines was explored with quantitative real-time PCR. The effect of circPIP5K1A on NSCLC was evaluated with circPIP5K1A silencing, miR-600 mimic transfection, and hypoxia-inducible factor (HIF)-1 alpha overexpression, followed by assessment of cell proliferation, metastasis, and tumorigenesis in nude mice. The subcellular localization of circPIP5K1A was evaluated via fluorescence in situ hybridization (FISH), and correlation between circPIP5K1A, miR-600, and HIF-1 alpha was assessed by luciferase assay. The data demonstrated that circPIP5K1A expression was increased in NSCLC cells. FISH showed that circPIP5K1A localized to the cytoplasm. The circPIP5K1A knockdown suppressed NSCLC cell metastasis and proliferation by promoting expression of miR-600. Overexpression of miR-600 inhibited HIF-1 alpha-mediated metastasis and proliferation of NSCLC cell by downregulating the endothelial mesenchymal transition-related proteins, Snail and vimentin, and upregulating E-cadherin. In vivo experiments illustrated that circPIP5K1A silence suppressed tumor growth and pulmonary metastasis. The circPIP5K1A may function as an miR-600 sponge to facilitate NSCLC proliferation and metastasis by promoting HIF-1 alpha. A bifluorescein reporter experiment confirmed that miR-600 was the circPIP5K1A target, and miR-600 interacted with the 3 ' untranslated region of HIF-1 alpha. These results show that circPIP5K1A acted as a tumor promoter through a novel circPIP5K1A/miR-600/HIF-1 alpha axis, which provides candidate markers and therapeutic targets for NSCLC.