Gu Hangzhi, Lin Rongrong, Zheng Feiyun, Zhang Qian
Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, No. 1 Fuxue Lane, Lucheng District, Wenzhou, Zhejiang, China.
J Mol Histol. 2021 Feb;52(1):31-44. doi: 10.1007/s10735-020-09921-5. Epub 2020 Oct 24.
As one of the most common cancers in female, ovarian cancer (OC) has become a serious public burden now. Mounting researches have indicated long noncoding RNAs (lncRNAs) can affect many biological processes including cancer development. LncRNA LBX2-AS1 was identified to be an oncogene in some cancers, but the role of LBX2-AS1 in OC remains to be elucidated. Bioinformatics analysis and experiments including ChIP, RT-qPCR, RIP, luciferase reporter, western blot and CCK-8 were performed to explore the role of LBX2-AS1 in OC. LBX2-AS1 expression was markedly increased in OC tissues and cell lines. Functionally, LBX2-AS1 silencing inhibited cell proliferation, migration and stemness but facilitated cell apoptosis in OC. Moreover, depletion of LBX2-AS1 suppressed tumor growth of OC in vivo. Mechanically, LBX2-AS1 was activated by transcriptional factor ELK1. ELK1 enhanced the expression of LBX2-AS1 in OC cells. In addition, miR-4784 was confirmed to be sponged by LBX2-AS1. There was a negative expression correlation between LBX2-AS1 and miR-4784 in OC tissues. Subsequently, KDM5C was identified to be a direct target of miR-4784 in OC cells. KDM5C was negatively regulated by miR-4784 and positively regulated by LBX2-AS1 in terms of expression level. Upregulation of KDM5C reversed the inhibitory effect of LBX2-AS1 depletion on the progression of OC. This study proved that ELK1 activated-LBX2-AS1 aggravated the progression of OC by targeting the miR-4784/KDM5C axis, suggesting that LBX2-AS2 may be a promising diagnostic biomarker of OC.
作为女性最常见的癌症之一，卵巢癌（OC）目前已成为一项严重的公共负担。越来越多的研究表明，长链非编码RNA（lncRNAs）可影响包括癌症发展在内的许多生物学过程。LncRNA LBX2-AS1在某些癌症中被鉴定为一种癌基因，但LBX2-AS1在卵巢癌中的作用仍有待阐明。进行了生物信息学分析以及包括染色质免疫沉淀（ChIP）、逆转录定量聚合酶链反应（RT-qPCR）、RNA免疫沉淀（RIP）、荧光素酶报告基因检测、蛋白质免疫印迹法（western blot）和细胞计数试剂盒-8（CCK-8）在内的实验，以探究LBX2-AS1在卵巢癌中的作用。LBX2-AS1在卵巢癌组织和细胞系中的表达显著增加。在功能上，LBX2-AS1沉默抑制了卵巢癌细胞的增殖、迁移和干性，但促进了细胞凋亡。此外，LBX2-AS1缺失在体内抑制了卵巢癌的肿瘤生长。从机制上来说，转录因子ELK1激活了LBX2-AS1。ELK1增强了LBX2-AS1在卵巢癌细胞中的表达。此外，证实LBX2-AS1可吸附miR-4784。在卵巢癌组织中，LBX2-AS1与miR-4784之间存在负表达相关性。随后，在卵巢癌细胞中鉴定出赖氨酸特异性去甲基化酶5C（KDM5C）是miR-4784的直接靶点。就表达水平而言，KDM5C受到miR-4784的负调控和LBX2-AS1的正调控。KDM5C的上调逆转了LBX2-AS1缺失对卵巢癌进展的抑制作用。本研究证明，ELK1激活的LBX2-AS1通过靶向miR-4784/KDM5C轴加重了卵巢癌的进展，提示LBX2-AS2可能是一种很有前景的卵巢癌诊断生物标志物。
