Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Cancer Lett. 2018 Nov 28;437:79-88. doi: 10.1016/j.canlet.2018.08.023. Epub 2018 Aug 27.
We previously identified a metastasis suppressor RAB37 small GTPase that regulated exocytosis of tissue inhibitor of metalloproteinases 1 (TIMP1) to suppress lung cancer metastasis. Here, we show that vesicle-associated membrane protein 8 (VAMP8), a v-SNARE (vesicle soluble N-ethylmaleimide-sensitive factor activating protein receptor), interacts with RAB37 and drives the secretion of TIMP1 to inhibit tumor metastases. Confocal and total internal reflection fluorescence microscopic images demonstrated that VAMP8 co-localized with RAB37 and facilitated trafficking of RAB37-TIMP1 vesicles. Reconstitution experiments using tail-vein injection and lung-to-lung metastasis in mice showed that VAMP8 was essential for RAB37-regulated vesicle trafficking of TIMP1 to suppress cancer metastasis. Lung cancer patients with low VAMP8 showed distant metastasis, poor overall survival and progression-free survival. Importantly, multivariate Cox regression analysis indicated that patients with low VAMP8/low RAB37 expression profile showed significantly high risk of death (hazard ratio = 3.42, P < 0.001) even after adjusting for tumor metastasis parameter. Our findings reveal that VAMP8 is a novel v-SNARE crucial for RAB37-mediated exocytic transport of TIMP1 to suppress lung tumor metastasis. VAMP8 possesses a tumor metastasis suppressor function with a prognostic value in lung cancer.
我们之前鉴定了一个转移抑制因子 RAB37 小分子 GTP 酶，它调控组织金属蛋白酶抑制剂 1（TIMP1）的胞吐作用，从而抑制肺癌转移。在这里，我们发现囊泡相关膜蛋白 8（VAMP8），一种 v-SNARE（囊泡可溶性 N-乙基马来酰亚胺敏感因子激活蛋白受体），与 RAB37 相互作用并驱动 TIMP1 的分泌，从而抑制肿瘤转移。共聚焦和全内反射荧光显微镜图像显示 VAMP8 与 RAB37 共定位，并促进 RAB37-TIMP1 囊泡的运输。使用尾静脉注射和小鼠肺到肺转移的重建实验表明，VAMP8 对于 RAB37 调节的 TIMP1 囊泡运输以抑制癌症转移是必不可少的。VAMP8 低表达的肺癌患者表现出远处转移、整体生存率和无进展生存率较差。重要的是，多变量 Cox 回归分析表明，即使在调整肿瘤转移参数后，VAMP8/低 RAB37 表达谱的患者死亡风险显著升高（危险比=3.42，P<0.001）。我们的研究结果表明，VAMP8 是一种新型 v-SNARE，对于 RAB37 介导的 TIMP1 胞吐运输抑制肺肿瘤转移至关重要。VAMP8 具有肿瘤转移抑制功能，并具有肺癌的预后价值。
