Li Min, Wang Jing, Ma Hongli, Gao Li, Zhao Kunxiang, Huang Tingting
Pathology Department, Jinan Second Maternal and Child Health Care Hospital, Jinan, China.
The Second Children & Women's Healthcare of Jinan City, Jinan, China.
Front Oncol. 2021 Nov 2;11:684477. doi: 10.3389/fonc.2021.684477. eCollection 2021.
Cervical cancer is one of the most severe and prevalent female malignancies and a global health issue. The molecular mechanisms underlying cervical cancer development are poorly investigated. As a type of extracellular membrane vesicles, EVs from cancer cells are involved in cancer progression by delivering regulatory factors, such as proteins, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). In this study, we identified an innovative function of extracellular vesicle (EV) lncRNA AGAP2-AS1 in regulating cervical cancer cell proliferation. The EVs were isolated from the cervical cancer cells and were observed by transmission electron microscopy (TEM) and were confirmed by analyzing exosome markers. The depletion of AGAP2-AS1 by siRNA significantly reduced its expression in the exosomes from cervical cancer and in the cervical cancer treated with AGAP2-AS1-knockdown exosomes. The expression of AGAP2-AS1 was elevated in the clinical cervical cancer tissues compared with the adjacent normal tissues. The depletion of EV AGAP2-AS1 reduced cell viabilities and Edu-positive cervical cancer cells, while it enhanced cervical cancer cell apoptosis. Tumorigenicity analysis in nude mice showed that the silencing of EV AGAP2-AS1 attenuated cervical cancer cell growth . Regarding the mechanism, we identified that AGAP2-AS1 increased SIRT1 expression by sponging miR-3064-5p in cervical cancer cells. The overexpression of SIRT1 or the inhibition of miR-3064-5p reversed EV AGAP2-AS1 depletion-inhibited cancer cell proliferation . Consequently, we concluded that EV lncRNA AGAP2-AS1 contributed to cervical cancer cell proliferation through regulating the miR-3064-5p/SIRT1 axis. The clinical values of EV lncRNA AGAP2-AS1 and miR-3064-5p deserve to be explored in cervical cancer diagnosis and treatments.
宫颈癌是最严重且常见的女性恶性肿瘤之一，是一个全球性的健康问题。目前对宫颈癌发生发展的分子机制研究较少。作为一种细胞外膜泡，癌细胞来源的细胞外囊泡（EVs）通过传递蛋白质、微小RNA（miRNAs）和长链非编码RNA（lncRNAs）等调节因子参与癌症进展。在本研究中，我们发现细胞外囊泡lncRNA AGAP2-AS1在调节宫颈癌细胞增殖方面具有创新功能。从宫颈癌细胞中分离出EVs，通过透射电子显微镜（TEM）观察，并通过分析外泌体标志物进行确认。用小干扰RNA（siRNA）敲低AGAP2-AS1可显著降低其在宫颈癌来源外泌体及用AGAP2-AS1敲低外泌体处理的宫颈癌中的表达。与相邻正常组织相比，AGAP2-AS1在临床宫颈癌组织中的表达升高。敲低EV AGAP2-AS1可降低细胞活力和Edu阳性宫颈癌细胞数量，同时增强宫颈癌细胞凋亡。裸鼠致瘤性分析表明，沉默EV AGAP2-AS1可减弱宫颈癌细胞生长。关于其机制，我们发现AGAP2-AS1通过在宫颈癌细胞中海绵化miR-3064-5p来增加SIRT1表达。SIRT1的过表达或miR-3064-5p的抑制可逆转EV AGAP2-AS1敲低抑制的癌细胞增殖。因此，我们得出结论，EV lncRNA AGAP2-AS1通过调节miR-3064-5p/SIRT1轴促进宫颈癌细胞增殖。EV lncRNA AGAP2-AS1和miR-3064-5p在宫颈癌诊断和治疗中的临床价值值得探索。
