Tu Guangxu, Peng Weilin, Peng Xiong, Zhao Zhenyu, Shi Shuai, Cai Qidong, He Boxue, Yin Wei, Peng Shaoliang, Wang Li, Yu Fenglei, Wang Xiang
Department of Thoracic Surgery, The Second Xiangya Hospital, Central South University Changsha 410011, Hunan, China.
Hunan Key Laboratory of Early Diagnosis and Precision Therapy, The Second Xiangya Hospital, Central South University Changsha 410011, Hunan, China.
Am J Cancer Res. 2023 Aug 15;13(8):3342-3367. eCollection 2023.
Emerging research indicates that circRNAs serve a crucial role in occurrence and development of cancers. This study aimed to uncover the biological role of hsa_circ_0000519 in the progression of LUAD (lung adenocarcinoma). hsa_circ_0000519 was identified by bioinformatic analysis, and its differential expression was validated in LUAD tissues and cell lines. CCK8, colony formation, wound healing, transwell assays, and xenograft tumor models were used to observe the biological functions of hsa_circ_0000519. FISH, RIP, dual luciferase reporter assays, and recovery experiments were implemented to explore the underlying mechanisms of hsa_circ_0000519. hsa_circ_0000519 was significantly upregulated in LUAD tissues and cell lines. The expression of hsa_circ_0000519 was positively correlated with T grade and TNM stage in patients with LUAD. Downregulation of hsa_circ_0000519 remarkably reduced cell proliferation, migration, invasion in vitro, and tumor growth in vivo. Mechanistic investigation demonstrated that hsa_circ_0000519 directly sponged hsa-miR-1296-5p to reduce its repressive impact on DARS as well as activate the PI3K/AKT/mTOR signaling pathway. The malignant phenotypes of LUAD cells induced by upregulation of hsa_circ_0000519 could be rescued by hsa-miR-1296-5p overexpression or knockdown of DARS. In conclusion, hsa_circ_0000519 promotes LUAD progression through the hsa-miR-1296-5p/DARS axis and may be expected as a novel biomarker and therapeutic for LUAD.
新兴研究表明,环状RNA在癌症的发生和发展中起关键作用。本研究旨在揭示hsa_circ_0000519在肺腺癌(LUAD)进展中的生物学作用。通过生物信息学分析鉴定出hsa_circ_0000519,并在LUAD组织和细胞系中验证了其差异表达。采用CCK8、集落形成、伤口愈合、Transwell实验和异种移植肿瘤模型来观察hsa_circ_0000519的生物学功能。实施荧光原位杂交(FISH)、RNA免疫沉淀(RIP)、双荧光素酶报告基因实验和回复实验以探究hsa_circ_0000519的潜在机制。hsa_circ_0000519在LUAD组织和细胞系中显著上调。hsa_circ_0000519的表达与LUAD患者的T分级和TNM分期呈正相关。下调hsa_circ_0000519可显著降低体外细胞增殖、迁移、侵袭以及体内肿瘤生长。机制研究表明,hsa_circ_0000519直接吸附hsa-miR-1296-5p以降低其对天冬酰胺-tRNA合成酶(DARS)的抑制作用,并激活PI3K/AKT/mTOR信号通路。hsa-miR-1296-5p过表达或敲低DARS可挽救由hsa_circ_0000519上调诱导的LUAD细胞的恶性表型。总之,hsa_circ_0000519通过hsa-miR-1296-5p/DARS轴促进LUAD进展,有望成为LUAD的新型生物标志物和治疗靶点。