Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan.
1] Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan [2] Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan.
Nat Commun. 2014 Sep 3;5:4804. doi: 10.1038/ncomms5804.
Rab small GTPases are master regulators of membrane trafficking and guide vesicle targeting. Recent publications show that Rab-controlled trafficking pathways are altered during tumorigenesis. However, whether any of the Rabs plays a metastasis suppressor role is least explored. Here we address the metastasis suppressive function of human Rab37 (hRAB37) using secretomics, cell, animal and clinical analyses. We show that tissue inhibitor of metalloproteinase 1 (TIMP1), a secreted glycoprotein that inhibits extracellular matrix turnover, is a novel cargo of hRAB37. hRAB37 regulates the exocytosis of TIMP1 in a nucleotide-dependent manner to inactivate matrix metalloproteinase 9 (MMP9) migration axis in vitro and in vivo. Dysfunction of hRAB37 or TIMP1 abrogates metastasis suppression. Lung cancer patients with metastasis and poor survival show low hRAB37 protein expression coinciding with low TIMP1 in tumours. Our findings identify hRAB37 as a novel metastasis suppressor Rab that functions through the TIMP1-MMP9 pathway and has significant prognostic power.
Rab 小分子 GTPases 是膜运输的主要调控因子，指导囊泡靶向。最近的出版物表明，Rab 控制的运输途径在肿瘤发生过程中发生改变。然而，至少还没有探索任何 Rab 是否具有转移抑制作用。在这里，我们使用分泌组学、细胞、动物和临床分析来研究人类 Rab37（hRAB37）的转移抑制功能。我们表明，组织金属蛋白酶抑制剂 1（TIMP1）是一种新型的 hRAB37 货物，它是一种分泌糖蛋白，可抑制细胞外基质的周转。hRAB37 以核苷酸依赖性方式调节 TIMP1 的胞吐作用，从而在体外和体内抑制基质金属蛋白酶 9（MMP9）迁移轴。hRAB37 或 TIMP1 的功能障碍会破坏转移抑制。具有转移和不良生存的肺癌患者的肿瘤中 hRAB37 蛋白表达水平低，同时 TIMP1 水平也低。我们的发现确定 hRAB37 为一种新型转移抑制 Rab，通过 TIMP1-MMP9 途径发挥作用，具有显著的预后能力。
