Recently, the long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was reported to be involved in the pathogenesis of several cancers, including human colorectal cancer (CRC). However, the molecular basis for cancer initiation, development, and progression remains unclear. In this study, we observe that upregulated PVT1 is associated with poor prognosis and bad clinicopathological features of CRC patients. In vitro means of PVT1 loss in a CRC cell line inhibit cell proliferation, migration, and invasion. Furthermore, dual-luciferase reporter and RNA pull-down assays indicated that PVT1 binds to miR-16-5p, which has been shown to play strong tumor suppressive roles in CRC. Targeted loss of miR-16-5p partially rescues the suppressive effect induced by PVT1 knockdown. Vascular endothelial growth factor A (VEGFA), a direct downstream target of miR-16-5p, was suppressed by PVT1 knockdown in CRC cells. Overexpression of VEGFA is known to modulate the AKT signaling cascade by activating vascular endothelial growth factor receptor 1 (VEGFR1). We, therefore, show that PVT1 loss combined with miR-16-5p overexpression reduces tumor volume maximally when propagated within a mouse xenograft model. We conclude that the PVT1-miR-16-5p/VEGFA/VEGFR1/AKT axis directly coordinates the response in CRC pathogenesis and suggest PVT1 as a novel target for potential CRC therapy.

最近，据报道，长非编码RNA（lncRNA）浆细胞瘤变体易位1（PVT1）参与多种癌症的发病机制，包括人类结直肠癌（CRC）。然而，癌症发生、发展和进展的分子基础仍不清楚。在这项研究中，我们观察到 PVT1 上调与 CRC 患者的不良预后和不良临床病理特征相关。 CRC 细胞系中 PVT1 缺失的体外方法会抑制细胞增殖、迁移和侵袭。此外，双荧光素酶报告基因和 RNA Pull-down 测定表明 PVT1 与 miR-16-5p 结合，miR-16-5p 已被证明在 CRC 中发挥强大的肿瘤抑制作用。 miR-16-5p 的靶向缺失部分挽救了 PVT1 敲低引起的抑制作用。血管内皮生长因子 A (VEGFA) 是 miR-16-5p 的直接下游靶标，在 CRC 细胞中被 PVT1 敲除所抑制。已知 VEGFA 的过度表达可通过激活血管内皮生长因子受体 1 (VEGFR1) 来调节 AKT 信号级联。因此，我们表明，当在小鼠异种移植模型中增殖时，PVT1 缺失与 miR-16-5p 过表达相结合可最大程度地减少肿瘤体积。我们得出结论，PVT1-miR-16-5p/VEGFA/VEGFR1/AKT 轴直接协调 CRC 发病机制中的反应，并建议 PVT1 作为潜在 CRC 治疗的新靶点。