Wang Jie, Shen Dongxiao, Li Shichao, Li Qiuying, Zuo Qingsong, Lu Jiahao, Tang Donghao, Feng Yuejiao, Yin Peihao, Chen Chao, Chen Teng
Department Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 200062, Shanghai, China.
Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 200062, Shanghai, China.
Cancer Gene Ther. 2023 Nov;30(11):1530-1542. doi: 10.1038/s41417-023-00657-4. Epub 2023 Aug 10.
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.
长链非编码RNA（lncRNAs）在人类癌症发展中起关键作用；然而，lncRNA LINC00665对胃癌（GC）进展的影响仍不清楚。在本研究中，我们发现LINC00665在GC中的表达高于正常胃黏膜组织，且LINC00665高表达与GC患者的不良预后相关。下调LINC00665可在体外抑制GC细胞的增殖、侵袭和迁移。肺转移动物模型显示，下调LINC00665可在体内减少GC的肺转移。从人恶性GC组织中生成肿瘤类器官，下调LINC00665可抑制GC组织类器官的生长。机制上，下调LINC00665可抑制GC细胞上皮-间质转化（EMT）。RNA下拉、RNA免疫沉淀（RIP）和RIP测序研究发现，LINC00665可与转录因子YBX1结合并形成正反馈前馈环。荧光素酶报告基因和染色质免疫沉淀（CHIP）结果表明，YBX1可调节Wnt3a的转录活性，下调LINC00665可阻断Wnt/β-连环蛋白信号通路的激活。总之，我们的结果确定了LINC00665与YBX1之间激活Wnt/β-连环蛋白信号通路的反馈环，这可能是抑制GC进展的一种潜在治疗方法。
