Abstract Lung cancer is a lethal malignancy. Plenty of circular RNAs (circRNAs) have been identified to be the vital regulators in lung cancer development. Here, we intended to clarify the functional role of circRNA HIPK3 (circHIPK3, also called hsa_circ_0021593) and its underlying mechanism of action. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was employed to evaluate the levels of circHIPK3 and miR-381-3p. Cell viability and apoptosis rate were monitored by Cell Counting Kit-8 assay and flow cytometry, respectively. Cell migration was estimated through the Transwell assay. To assess glycolysis, commercial kits were utilized to measure the levels of glucose and lactate and the enzyme activity of hexokinase-2 (HK2). Expression of related proteins was detected via western blot analysis. The target connection between circHIPK3 and miR-381-3p was validated by dual-luciferase reporter, RIP, and pull-down assays. The role of circHIPK3 in vivo was determined via the xenograft assay. CircHIPK3 was upregulated, while miR-381-3p was downregulated in lung cancer tissues and cells. And circHIPK3 deficiency inhibited lung cancer progression by lowering cell proliferation, migration, glycolysis, and promoting apoptosis of lung cancer cells in vitro. MiR-381-3p was a target of circHIPK3, and miR-381-3p interference alleviated circHIPK3 knockdown-induced lung cancer progression inhibition. CircHIPK3 could activate the protein kinase B/mammalian target of rapamycin (AKT/mTOR) signaling pathway. Moreover, circHIPK3 knockdown suppressed tumor growth in vivo by inactivating the AKT/mTOR signaling pathway. In conclusion, the silencing of circHIPK3 inhibited lung cancer progression, at least in part, by sponging miR-381-3p and inactivating the AKT/mTOR signaling pathway.

中文翻译：

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CircHIPK3/miR-381-3p轴通过调节AKT/mTOR信号通路调控肺癌细胞的增殖、迁移和糖酵解

摘要 肺癌是一种致命的恶性肿瘤。大量的环状 RNA (circRNA) 已被确定为肺癌发展的重要调节因子。在这里，我们旨在阐明circRNA HIPK3（circHIPK3，也称为hsa_circ_0021593）的功能作用及其潜在作用机制。采用定量逆转录聚合酶链反应 (qRT-PCR) 来评估 circHIPK3 和 miR-381-3p 的水平。细胞活力和凋亡率分别通过 Cell Counting Kit-8 测定和流式细胞术监测。通过 Transwell 测定估计细胞迁移。为了评估糖酵解，使用商业试剂盒来测量葡萄糖和乳酸的水平以及己糖激酶-2 (HK2) 的酶活性。通过蛋白质印迹分析检测相关蛋白的表达。circHIPK3 和 miR-381-3p 之间的靶标连接通过双荧光素酶报告基因、RIP 和下拉分析进行了验证。circHIPK3 在体内的作用是通过异种移植试验确定的。在肺癌组织和细胞中，CircHIPK3 被上调，而 miR-381-3p 被下调。在体外，circHIPK3缺陷通过降低细胞增殖、迁移、糖酵解和促进肺癌细胞凋亡来抑制肺癌进展。MiR-381-3p 是 circHIPK3 的靶标，miR-381-3p 干扰减轻了 circHIPK3 敲低诱导的肺癌进展抑制。CircHIPK3 可以激活雷帕霉素 (AKT/mTOR) 信号通路的蛋白激酶 B/哺乳动物靶点。此外，circHIPK3敲低通过灭活AKT/mTOR信号通路抑制体内肿瘤生长。综上所述，