Zhu Tianyu, Wang Zhuoyin, Wang Guojun, Hu Zhihao, Ding Hengxuan, Li Ruixin, Sun Junfeng
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, PR China.
J Adv Res. 2020 Jun 24;28:7-15. doi: 10.1016/j.jare.2020.06.006. eCollection 2021 Feb.
LncRNA (Long non-coding RNA) ZFAS1 (zinc finger antisense 1) functions as the oncogene in multiple cancers, including gastric cancer. However, its function and underlying mechanism in the GCA (gastric cardia adenocarcinoma), the most aggressive type of gastric cancer, remain unknown. We demonstrated here that the LncRNA ZFAS1 was up-regulated in GCA tissues. Furthermore, the elevated level of ZFAS1 was significantly associated with the GCA metastasis and cancer recurrence. It was also demonstrated to be an independent prognostic indicator of disease-free survival and overall survival for GCA patients. RNA sequencing showed that the up-regulated ZFAS1 was tightly associated with the down-regulated hypoxia inducible factor 1 (HIF1) and up-regulated EPAS1 (Endothelial PAS domain protein 1, also known as HIF2). In vitro studies showed that the ZFAS1 could bind to EPAS1, enhance its abilities to epigenetically silence the HIF1, and promote its own expression in GCA cell lines. In the animal model, co-delivering the EPAS1 and the ZFAS1 antisense oligos could significantly boost up their therapeutic effects on tumor growth. Thus, targeting ZFAS1 and EPAS1 might be an alternative therapeutic option in GCA.
长链非编码RNA（LncRNA）ZFAS1（锌指反义1）在包括胃癌在内的多种癌症中发挥癌基因作用。然而，其在最具侵袭性的胃癌类型——贲门腺癌（GCA）中的功能及潜在机制仍不清楚。我们在此证明，LncRNA ZFAS1在GCA组织中上调。此外，ZFAS1水平升高与GCA转移和癌症复发显著相关。它还被证明是GCA患者无病生存期和总生存期的独立预后指标。RNA测序显示，上调的ZFAS1与下调的缺氧诱导因子1（HIF1）和上调的内皮PAS结构域蛋白1（EPAS1，也称为HIF2）密切相关。体外研究表明，ZFAS1可与EPAS1结合，增强其对HIF1进行表观遗传沉默的能力，并促进其在GCA细胞系中的自身表达。在动物模型中，共同递送EPAS1和ZFAS1反义寡核苷酸可显著增强它们对肿瘤生长的治疗效果。因此，靶向ZFAS1和EPAS1可能是GCA的一种替代治疗选择。
