Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
Cancer Metastasis Institute, Fudan University, Shanghai, 200040, China.
Oncogene. 2018 Jul;37(30):4094-4109. doi: 10.1038/s41388-018-0250-z. Epub 2018 Apr 30.
Angiogenesis can aggravate gastric cancer progression. LncRNAs exert important roles in regulating various cancer behaviors. However, the functions and mechanisms of lncRNAs in angiogenesis remain largely unknown. Here we demonstrated that lncRNA PVT1 was upregulated and significantly associated with high-microvessel density and poor prognosis in gastric cancer. Through gain- and loss-of PVT1 expression, we found PVT1 could obviously induce angiogenesis within tumors, in addition to promoting tumor growth in vitro and in vivo. Mechanistically, PVT1 directly interacted with the signal transducer activator phospho-STAT3 in the nucleus, and increased its protein stability by protecting it from poly-ubiquitination and proteasome-dependent degradation. The binding of PVT1 activated the STAT3 signalling pathway, and successively elevated VEGFA expression to stimulate angiogenesis. The positive correlation of PVT1 and VEGFA expression was also verified in gastric cancer specimens, and high levels of PVT1 and VEGFA in combination frequently predicted shorter survival time. Moreover, we revealed that PVT1 was a STAT3-responsive lncRNA, as STAT3 could occupy the PVT1 promoter to facilitate its transcription. The positive feed-back loop of PVT1 and STAT3 continuously enhanced the oncogenic effects. Collectively, our study first elucidates the mechanism of PVT1-mediated angiogenesis via evoking the STAT3/VEGFA signalling axis, which provides promising target for developing new therapeutic strategy in gastric cancer.
血管生成可加重胃癌进展。长链非编码 RNA（lncRNA）在调节多种癌症行为方面发挥着重要作用。然而，lncRNA 在血管生成中的功能和机制在很大程度上仍然未知。在这里，我们证明 lncRNA PVT1 在胃癌中上调，并与高微血管密度和预后不良显著相关。通过过表达和敲低 PVT1 的表达，我们发现 PVT1 可以明显诱导肿瘤内血管生成，除了促进肿瘤在体外和体内的生长。在机制上，PVT1 直接与核内信号转导激活物磷酸化 STAT3 相互作用，并通过保护其免受多泛素化和蛋白酶体依赖性降解来增加其蛋白稳定性。PVT1 的结合激活了 STAT3 信号通路，并相继上调 VEGFA 表达以刺激血管生成。在胃癌标本中也验证了 PVT1 和 VEGFA 表达的正相关性，并且 PVT1 和 VEGFA 的高水平组合经常预测较短的生存时间。此外，我们揭示了 PVT1 是一种 STAT3 反应性 lncRNA，因为 STAT3 可以占据 PVT1 启动子以促进其转录。PVT1 和 STAT3 的正反馈循环不断增强致癌作用。总之，我们的研究首次通过引发 STAT3/VEGFA 信号通路阐明了 PVT1 介导的血管生成的机制，为开发胃癌新的治疗策略提供了有希望的靶点。
