环状RNA（circRNA）等非编码RNA在人体内含量丰富，影响多种疾病的发生和发展。非小细胞肺癌（NSCLC）是最常见的恶性肿瘤之一。关于circRNA在肺癌中的功能和机制的信息有限；因此，这个话题需要更多的探索。本研究的目的是鉴定肺癌中异常表达的circRNA，揭示其在NSCLC进展中的作用，为肺癌的诊断和治疗提供新靶点。采用高通量测序技术分析肺癌患者中差异性circRNA表达。采用 qRT-PCR 测定肺癌组织和血浆样本中 circHERC1 的水平。通过功能获得和丧失实验观察circHERC1对体外和体内肺癌细胞生长、侵袭和转移的影响。从机制上讲，进行了双荧光素酶报告基因测定、荧光原位杂交 (FISH)、RNA 免疫沉淀 (RIP) 和 RNA Pull-down 实验，以确认 circHERC1 的潜在机制。 FOXO1 的核细胞质定位通过核细胞质分离和免疫荧光测定。通过 RNA Pull-down、RNA 免疫沉淀 (RIP) 和蛋白质印迹测定验证了 circHERC1 与 FOXO1 的相互作用。通过裸鼠皮下和尾静脉注射验证circHERC1在体内的增殖和迁移能力。circHERC1在肺癌组织和细胞中显着上调，circHERC1的异位表达显着促进增殖、侵袭和转移，并抑制肺细胞凋亡体外和体内的癌细胞。然而，敲除 circHERC1 会产生相反的效果。 CircHERC1主要分布在细胞质中。进一步的机制研究表明，circHERC1作为miR-142-3p的竞争性内源RNA，缓解miR-142-3p对其靶标HMGB1的抑制作用，激活MAPK/ERK和NF-κB通路，促进细胞迁移和侵袭。更重要的是，我们发现circHERC1可以结合FOXO1并将其隔离在细胞质中，调节反馈AKT通路。 FOXO1在细胞质中的积累和核排斥促进细胞增殖并抑制细胞凋亡。 CircHERC1是一种促进NSCLC肿瘤功能的新型circRNA，可能作为NSCLC潜在的预后生物标志物和治疗靶点。CircHERC1是一种促进NSCLC肿瘤功能的新型circRNA，可能作为NSCLC潜在的诊断生物标志物和治疗靶点。我们的研究结果表明，circHERC1通过调节miR-142-3p/HMGB1轴并激活MAPK/ERK和NF-κB通路来促进NSCLC细胞的侵袭和转移。此外，circHERC1 可通过将 FOXO1 隔离在细胞质中来调节 AKT 活性和 BIM 转录，从而促进细胞增殖并抑制细胞凋亡。© 2023。作者。

Noncoding RNAs such as circular RNAs (circRNAs) are abundant in the human body and influence the occurrence and development of various diseases. Non-small cell lung cancer (NSCLC) is one of the most common malignant cancers. Information on the functions and mechanism of circRNAs in lung cancer is limited; thus, the topic needs more exploration. The purpose of this study was to identify aberrantly expressed circRNAs in lung cancer, unravel their roles in NSCLC progression, and provide new targets for lung cancer diagnosis and therapy.High-throughput sequencing was used to analyze differential circRNA expression in patients with lung cancer. qRT‒PCR was used to determine the level of circHERC1 in lung cancer tissues and plasma samples. Gain- and loss-of-function experiments were implemented to observe the impacts of circHERC1 on the growth, invasion, and metastasis of lung cancer cells in vitro and in vivo. Mechanistically, dual luciferase reporter assays, fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down experiments were performed to confirm the underlying mechanisms of circHERC1. Nucleocytoplasmic localization of FOXO1 was determined by nucleocytoplasmic isolation and immunofluorescence. The interaction of circHERC1 with FOXO1 was verified by RNA pull-down, RNA immunoprecipitation (RIP) and western blot assays. The proliferation and migration of circHERC1 in vivo were verified by subcutaneous and tail vein injection in nude mice.CircHERC1 was significantly upregulated in lung cancer tissues and cells, ectopic expression of circHERC1 strikingly facilitated the proliferation, invasion and metastasis, and inhibited the apoptosis of lung cancer cells in vitro and in vivo. However, knockdown of circHERC1 exerted the opposite effects. CircHERC1 was mainly distributed in the cytoplasm. Further mechanistic research indicated that circHERC1 acted as a competing endogenous RNA of miR-142-3p to relieve the repressive effect of miR-142-3p on its target HMGB1, activating the MAPK/ERK and NF-κB pathways and promoting cell migration and invasion. More importantly, we found that circHERC1 could bind FOXO1 and sequester it in the cytoplasm, adjusting the feedback AKT pathway. The accumulation of FOXO1 in the cytosol and nuclear exclusion promoted cell proliferation and inhibited apoptosis. CircHERC1 is a new circRNA that promotes tumor function in NSCLC and may serve as a potential prognostic biomarker and therapeutic target for NSCLC.CircHERC1 is a new circRNA that promotes tumor function in NSCLC and may serve as a potential diagnosis biomarker and therapeutic target for NSCLC. Our findings indicate that circHERC1 facilitates the invasion and metastasis of NSCLC cells by regulating the miR-142-3p/HMGB1 axis and activating the MAPK/ERK and NF-κB pathways. In addition, circHERC1 can promote cell proliferation and inhibit apoptosis by sequestering FOXO1 in the cytoplasm to regulate AKT activity and BIM transcription.© 2023. The Author(s).