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The hypoxia microenvironment induces the expression of HIF1 and EPAS1 in GCA. During tumor development, the EPAS1 suppresses the expression of HIF1, resulting in the dominant form of HIFs switching from HIF1 to EPAS1. LncRNA ZFAS1 binds to EPAS1, facilitating the HIF1 suppression, EPAS1 up-regulation, and the switching from HIF1 to EPAS1. 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. In the current study, the expression level of LncRNA ZFAS1 was quantified in 762 GCA tissues and the paired adjacent non-tumor tissues. The expression level of LncRNA ZFAS1 was quantified in 762 GCA tissues and the paired adjacent non-tumor tissues, and further confirmed using in vitro cell and animal model based assays. 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, codelivering 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. [ABSTRACT FROM AUTHOR]