报道Rab37介导的组织金属蛋白酶抑制因子1（TIMP1）的胞外分泌，TIMP1是一种炎症细胞因子，并受血清耗竭条件的影响，可抑制肺癌细胞转移。此外，饥饿也是自噬活性的一种刺激。我们在此揭示饥饿激活Rab37并诱导自噬的过程。我们采用过表达/敲低系统来确定自噬和Rab37在体内外的关系。自噬活性通过免疫印迹、透射电镜、自噬体净化和共聚焦显微镜下的免疫荧光法进行检测。采用肺到肺转移小鼠模型来阐明自噬和Rab37在肺癌中的作用。分析了临床肺癌患者标本和在线大型数据库。 我们首先证明活性Rab37可以增加LC3-II蛋白水平（自噬体标记物）和TIMP1分泌。因此，Rab37基因表达的沉默减轻了Rab37和LC3-II水平以及TIMP1分泌，并且在此类条件下，诱导自噬不能增加TIMP1的胞外分泌。此外，在低活性Rab37（Q89L）携带的肺癌细胞中沉默Atg5或Atg7基因会导致自噬活性和TIMP1分泌的降低。在肺到肺转移小鼠模型中，amiodarone诱导的自噬伴随TIMP1表达的增加，导致肿瘤结节和癌细胞转移的减少。沉默Atg5或Atg7基因会逆转这些现象。值得注意的是，单独增加自噬活性在Rab37或Sec22b沉默条件下对TIMP1的分泌没有影响。我们进一步检测了LC3与Rab37或TIMP1的共定位，鉴定了携带活性Rab37基因的肺癌细胞中的Rab37和Sec22b蛋白质在纯化的自噬体中的存在，并确认这些蛋白质参与TIMP1的分泌。我们发现，在肿瘤中的自噬活性显著低于非肿瘤部分，并与整体肺癌患者的生存率有关。 我们首次报道了自噬在Rab37依赖的方式中促进TIMP1分泌和肺癌细胞转移的作用，这一现象在肺到肺小鼠模型中也得到了证实。©2022.作者（们）。

Rab37-mediated exocytosis of tissue inhibitor of metalloproteinase 1 (TIMP1), an inflammatory cytokine, under serum-depleted conditions which leads to suppression of lung cancer cell metastasis has been reported. Starvation is also a stimulus of autophagic activity. Herein, we reveal that starvation activates Rab37 and induces autophagy.We used an overexpression/knockdown system to determine the relationship between autophagy and Rab37 in vitro and in vivo. The autophagy activity was detected by immunoblotting, transmission electron microscope, autophagosome purification, and immunofluorescence under the confocal microscope. Lung-to-lung metastasis mouse model was used to clarify the role of autophagy and Rab37 in lung cancer. Clinical lung cancer patient specimens and an online big database were analyzed.Initially, we demonstrated that active-form Rab37 increased LC3-II protein level (the marker of autophagosome) and TIMP1 secretion. Accordingly, silencing of Rab37 gene expression alleviated Rab37 and LC3-II levels as well as TIMP1 secretion, and induction of autophagy could not increase TIMP1 exocytosis under such conditions. Moreover, silencing the Atg5 or Atg7 gene of lung cancer cells harboring active-mutant Rab37 (Q89L) led to decreased autophagy activity and TIMP1 secretion. In the lung-to-lung metastasis mouse model, increased TIMP1 expression accompanied by amiodarone-induced autophagy led to decreased tumor nodules and cancer cell metastasis. These phenomena were reversed by silencing the Atg5 or Atg7 gene. Notably, increasing autophagy activity alone showed no effect on TIMP1 secretion under either Rab37 or Sec22b silencing conditions. We further detected colocalization of LC3 with either Rab37 or TIMP1, identified Rab37 and Sec22b proteins in the purified autophagosomes of the lung cancer cells harboring the active-form Rab37 gene, and confirmed that these proteins are involved in the secretion of TIMP1. We reveal that autophagic activity was significantly lower in the tumors compared to the non-tumor parts and was associated with the overall lung cancer patient survival rate.We are the first to report that autophagy plays a promoting role in TIMP1 secretion and metastasis in a Rab37-dependent manner in lung cancer cells and the lung-to-lung mouse model.© 2022. The Author(s).