Duan Meng, Fang Meixia, Wang Changhe, Wang Hongyan, Li Meng
Department of Gynecology, Jining No. 1 People's Hospital, Jining, Shandong 272000, People's Republic of China.
Cancer Manag Res. 2020 Mar 24;12:2141-2154. doi: 10.2147/CMAR.S229013. eCollection 2020.
Long noncoding RNA (lncRNA) deregulation is frequent in human ovarian cancers (OCs), but the role of specific miRNAs involved in this disease remains elusive. LncRNA EMX2OS was previously reported to act as an oncogene in human cancers. However, their accurate expression, function and underlying mechanisms in OC are largely unclear.
The levels of EMX2OS in OC tissues and cell lines were determined by quantitative real-time PCR, and the function of EMX2OS was then analyzed both in vitro and in vivo. Luciferase assays and immunoprecipitation assays were performed to analyze the association between EMX2OS and miR-654 expression in OC cells.
EMX2OS is overexpressed in human ovarian cancer tissues. Knockdown of EMX2OS reduced, while overexpression of EMX2OS enhanced the proliferation, invasion and sphere formation of OC cells. In addition, EMX2OS enhanced tumor growth in an in vivo xenograft model of human OC. We discovered that EMX2OS directly binds to miR-654 and suppresses its expression, thus leading to the upregulation of AKT3, which served as a direct target of miR-654. Moreover, miR-654 inhibited cell proliferation, invasion and sphere formation, and restoration of AKT3 reversed the effects of EMX2OS silencing or miR-654 overexpression. Furthermore, PD-L1 was identified as the key oncogenic component acting downstream of AKT3 in OC cells. Ectopic expression of PD-L1 reversed the anti-cancer functions by EMX2OS knockdown, AKT3 silencing or miR-654 upregulation in OC cells.
These results demonstrated that the EMX2OS/miR-654/AKT3/PD-L1 axis confers aggressiveness in ovarian cancer and may represent a therapeutic target for OC metastasis.
长链非编码RNA（lncRNA）失调在人类卵巢癌（OC）中很常见，但参与该疾病的特定微小RNA（miRNA）的作用仍不清楚。lncRNA EMX2OS先前被报道在人类癌症中作为癌基因发挥作用。然而，其在OC中的准确表达、功能及潜在机制在很大程度上尚不清楚。
通过定量实时PCR测定OC组织和细胞系中EMX2OS的水平，然后在体外和体内分析EMX2OS的功能。进行荧光素酶报告基因检测和免疫沉淀检测，以分析OC细胞中EMX2OS与miR - 654表达之间的关联。
EMX2OS在人类卵巢癌组织中过表达。敲低EMX2OS可降低OC细胞的增殖、侵袭和球体形成能力，而EMX2OS的过表达则增强这些能力。此外，在人类OC的体内异种移植模型中，EMX2OS促进肿瘤生长。我们发现EMX2OS直接与miR - 654结合并抑制其表达，从而导致作为miR - 654直接靶点的AKT3上调。此外，miR - 654抑制细胞增殖、侵袭和球体形成，而恢复AKT3可逆转EMX2OS沉默或miR - 654过表达的影响。此外，PD - L1被确定为OC细胞中AKT3下游起作用的关键致癌成分。异位表达PD - L1可逆转OC细胞中EMX2OS敲低、AKT3沉默或miR - 654上调的抗癌功能。
这些结果表明，EMX2OS/miR - 654/AKT3/PD - L1轴赋予卵巢癌侵袭性，可能代表OC转移的治疗靶点。
