VPS35 是逆转录酶复合体的关键亚基，负责识别货物中的胞质检索信号，并参与神经退行性疾病和肿瘤进展。然而，VPS35在胃癌（GC）中的功能和分子机制仍然很大程度上未知。在这里，我们证明 VPS35 在 GC 中显着上调，这与较差的生存率相关。 VPS35在体外和体内均促进GC细胞增殖和转移。从机制上讲，VPS35 通过整合素介导的由外向内信号传导激活 FAK-SRC 激酶，从而激活 YAP 并随后诱导肿瘤细胞中的 IL-6 表达。此外，结合MGC-803细胞的质谱分析和生物信息学分析，我们发现GC细胞中VPS35的磷酸化增强，并且磷酸化的VPS35与ITGB3的相互作用增强。 VPS35与ITGB3相互作用并影响GC细胞中ITGB3的回收。功能获得和丧失实验表明，VPS35 通过 IL-6/STAT3 途径促进肿瘤增殖和转移。有趣的是，我们还发现STAT3直接与VPS35启动子结合并增加VPS35转录，从而建立正调节反馈环。此外，我们证明 VPS35 敲低使 GC 细胞对 5-FU 和顺铂敏感。这些发现提供了 VPS35 促进肿瘤增殖和转移的证据，并强调了靶向 VPS35 和 IL-6/STAT3 介导的肿瘤相互作用作为 GC 有前途的治疗策略的潜力。© 2023。作者。

VPS35 is a key subunit of the retromer complex responsible for recognising cytosolic retrieval signals in cargo and is involved in neurodegenerative disease and tumour progression. However, the function and molecular mechanism of VPS35 in gastric cancer (GC) remains largely unknown. Here, we demonstrated that VPS35 was significantly upregulated in GC, which was associated with poor survival. VPS35 promoted GC cell proliferation and metastasis both in vitro and in vivo. Mechanistically, VPS35 activated FAK-SRC kinases through integrin-mediated outside-in signalling, leading to the activation of YAP and subsequent IL-6 expression induction in tumour cells. What's more, combined mass spectrometry analysis of MGC-803 cell and bioinformatic analysis, we found that phosphorylation of VPS35 was enhanced in GC cells, and phosphorylated VPS35 has enhanced interaction with ITGB3. VPS35 interacted with ITGB3 and affected the recycling of ITGB3 in GC cells. Gain- and loss-of-function experiments revealed that VPS35 promoted tumour proliferation and metastasis via the IL-6/STAT3 pathway. Interestingly, we also found that STAT3 directly bound to the VPS35 promoter and increased VPS35 transcription, thereby establishing a positive regulatory feedback loop. In addition, we demonstrated that VPS35 knockdown sensitised GC cells to 5-FU and cisplatin. These findings provide evidence that VPS35 promotes tumour proliferation and metastasis, and highlight the potential of targeting VPS35- and IL-6/STAT3-mediated tumour interactions as promising therapeutic strategies for GC.© 2023. The Author(s).