长链非编码RNA（lncRNA）在人类癌症发展中起着关键作用；然而，lncRNA LINC00665对胃癌（GC）的进展的影响仍不清楚。在本研究中，我们发现LINC00665在GC中的表达水平高于正常胃粘膜组织，并且较高的LINC00665表达与GC患者预后不良相关。下调LINC00665抑制了体外GC细胞的增殖、侵袭和迁移。肺转移动物模型显示，下调LINC00665可以减少GC的肺转移。从人类恶性GC组织生成了肿瘤器官样体，下调LINC00665可以抑制GC组织器官样体的生长。机制上，下调LINC00665可以抑制GC细胞的EMT。RNA pulldown、RIP和RIP-seq研究发现LINC00665能够结合转录因子YBX1并形成正反馈环路。荧光素酶报告和CHIP结果显示YBX1能够调节Wnt3a的转录活性，下调LINC00665能够阻断Wnt/β-连环蛋白信号的激活。总之，我们的结果确定了LINC00665和YBX1之间的反馈环路，激活了Wnt/β-连环蛋白信号，可能是抑制GC进展的潜在治疗方法。© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

Long noncoding RNAs (lncRNAs) play a key role in human cancer development; nevertheless, the effect of lncRNA LINC00665 on the progression of gastric cancer (GC) still unclear. In this study, we found that LINC00665 expression is upregulated in GC than normal gastric mucosa tissues and higher LINC00665 expression is associated with a poor prognosis in GC patients. Downregulated LINC00665 inhibited GC cells proliferation, invasion, and migration in vitro. Pulmonary metastasis animal models showed that downregulated LINC00665 could reduce the lung metastasis of GC in vivo. Tumor organoids were generated from human malignant GC tissues, downregulated LINC00665 could inhibit the growth of the organoids of GC tissues. Mechanistically, downregulated LINC00665 could inhibit GC cells EMT. RNA pulldown, RIP, and RIP-seq studies found that LINC00665 can bind to the transcription factor YBX1 and form a positive feed-forward loop. The luciferase reporter and CHIP results showed that YBX1 could regulate the transcriptional activity of Wnt3a, and downregulation of LINC00665 could block the activation of Wnt/β-catenin signaling. In conclusion, our results identified a feedback loop between LINC00665 and YBX1 that activates Wnt/β-catenin signaling, and it may be a potential therapeutic approach to suppress GC progression.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.