VAMP8, a vesicle-SNARE required for RAB37-mediated exocytosis, possesses a tumor metastasis suppressor function

• Published in: Cancer letters Vol. 437; pp. 79 - 88
• Main Authors: Wang, Yu-Shiuan, Tzeng, Hong-Tai, Tsai, Chung-Han, Cheng, Hung-Chi, Lai, Wu-Wei, Liu, Hsiao-Sheng, Wang, Yi-Ching
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.11.2018; Elsevier Limited
• Subjects: Exocytosis; Fluorescence; Guanosine triphosphatases; Immunoglobulins; Insulin; Lung cancer; Medical prognosis; Membrane proteins; Metastases; Metastasis; Motility; Multivariate analysis; N-Ethylmaleimide-sensitive protein; Prognosis; Protein expression; Proteins; RAB37; Regression analysis; Secretion; Signal transduction; SNAP receptors; Software; Survival; TIMP1; Tissue inhibitor of metalloproteinase 1; VAMP8; United States > US; Taiwan; VAMP8; Prognosis; RAB37; IHC; SNAREs; IP; CM; TIMP1; Metastasis; Exocytosis; IF; TIRF
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2018.08.023

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. •VAMP8, a vesicle-SNARE, shows tumor metastasis suppressive functions in lung cancer.•Concordant low VAMP8/Rab37 expression profile correlates with poor outcome.•VAMP8 is required for Rab37-mediated metastatic suppression in vivo.•Silence of VAMP8 abolishes Rab37-mediated exocytosis of metastasis suppressor TIMP1.•VAMP8 co-localizes with Rab37 in a GTPase-dependent manner.