Purpose

Vasculogenic mimicry (VM), a vessel-like network formed by highly aggressive tumor cells, plays an important role in accelerating cancer progression. This special vascularization pattern is closely associated with a poor prognosis in various cancers. As yet, however, the regulatory mechanism of VM formation is largely unknown. In this study, we assess whether the long noncoding RNA PVT1 is involved in VM generation in gastric cancer.

Methods

VM formation was determined by immunohistochemistry using PAS/CD31 double staining in gastric cancers and Matrigel tube formation in vitro. qRT-PCR and Western blotting were used to assess mRNA and protein expression. Interaction between PVT1 and STAT3 was determined using a RNA pull-down assay. Luciferase reporter and chromatin immunoprecipitation assays were performed to evaluate transcriptional activity of STAT3 on the Slug gene promoter.

Results

We found that PVT1 can induce VM generation both in vitro and in vivo. Mechanistically, we found that PVT1 interacted with and activated STAT3 through a 850–1770 nt fragment. PVT1 facilitated STAT3 recruitment to the Slug promoter and transcriptionally enhanced Slug expression, thereby triggering epithelial-to-mesenchymal transition (EMT) and VM capillary formation. STAT3 inhibition effectively blocked PVT1-mediated VM. In primary gastric cancer samples, a positive correlation was found between PVT1 and Slug upregulation, and patients with a high PVT1 and Slug expression exhibited markedly shorter survival times.

Conclusion

Our results shed light on the role of PVT1 in gastric cancer cell-dependent VM formation. Our findings provide valuable clues for the design of new anti-angiogenic therapeutic strategies. The PVT1/STAT3 axis may serve as a potential target in gastric cancer treatment.

中文翻译：

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LncRNA PVT1通过激活STAT3 / Slug轴和上皮向间充质转化来诱导积极的血管生成模拟物形成。

目的

血管生成模拟物（VM）是由高度侵袭性的肿瘤细胞形成的类似血管的网络，在加速癌症进展中起着重要作用。这种特殊的血管化模式与各种癌症的不良预后密切相关。但是，到目前为止，VM形成的调控机制还不清楚。在这项研究中，我们评估了长非编码RNA PVT1是否参与胃癌VM的产生。

方法

通过免疫组织化学使用PAS / CD31双重染色在胃癌和体外Matrigel管形成中确定VM的形成。使用qRT-PCR和Western blotting评估mRNA和蛋白表达。使用RNA下拉测定法确定PVT1和STAT3之间的相互作用。进行荧光素酶报告基因和染色质免疫沉淀测定以评估STAT3对Slug基因启动子的转录活性。

结果

我们发现PVT1可以在体外和体内诱导VM生成。从机理上讲，我们发现PVT1通过850-1770 nt片段与STAT3相互作用并被激活。PVT1促进STAT3募集到Slug启动子并转录增强Slug表达，从而触发上皮-间充质转化（EMT）和VM毛细血管形成。STAT3抑制有效地阻止了PVT1介导的VM。在原发性胃癌样本中，PVT1与Slug上调之间存在正相关，而PVT1和Slug表达高的患者的生存时间明显缩短。

结论

我们的研究结果揭示了PVT1在胃癌细胞依赖型VM形成中的作用。我们的发现为设计新的抗血管生成治疗策略提供了有价值的线索。PVT1 / STAT3轴可作为胃癌治疗的潜在靶标。