通过内体囊泡回收整合素对于癌细胞的迁移至关重要，这会导致胰腺癌的转移和毁灭性的癌症相关死亡。因此，需要开发针对内体囊泡再循环的新的诊断和治疗分子。对TCGA、ICGC、GSE21501、GSE28735和GENT等公共数据库进行分析，以推导出诊断和治疗靶点。为了揭示分子靶点的生物学作用和潜在机制，进行了各种分子生物学实验。首先，我们确定了UNC13D在胰腺癌患者（n = 824）中的过度表达及其在四种独立胰腺癌中的预后意义和高风险比（HR）队列（TCGA，n = 178，p = 0.014，HR = 3.629；ICGC，n = 91，p = 0.000，HR = 4.362；GSE21501，n = 102，p = 0.002， = 2.339，n = 45； p = 0.022，HR = 2.681）。此外，其表达与胰腺癌的临床病理进展相关。进一步的生物学研究表明，UNC13D 通过调节 FAK 磷酸化，将回收内体的胞吐作用与粘着斑周转耦合起来，从而调节胰腺癌细胞的迁移。免疫沉淀和免疫细胞化学显示整合素回收过程中内体中 RAB11-UNC13D-FAK 轴的形成。我们观察到 UNC13D 直接与 FAK 的 FERM 结构域相互作用，并以钙依赖性方式调节 FAK 磷酸化。最后，我们发现 UNC13D 和 FAK 的共表达表现出最差的生存率（TCGA，p = 0.000；ICGC，p = 0.036；GSE28735，p = 0.006）。我们强调，UNC13D 作为一种新型预后因素，通过以下方式促进胰腺癌进展：通过 RAB11-UNC13D-FAK 轴将整合素回收与粘着斑周转相结合以实现胰腺癌细胞的迁移。© 2024。作者。

Recycling of integrin via endosomal vesicles is critical for the migration of cancer cells, which leads to the metastasis of pancreatic cancer and devastating cancer-related death. So, new diagnostic and therapeutic molecules which target the recycling of endosomal vesicles need to be developed.Public databases including TCGA, ICGC, GSE21501, GSE28735, and GENT are analyzed to derive diagnostic and therapeutic targets. To reveal biological roles and underlying mechanisms of molecular targets, various molecular biological experiments were conducted.First, we identified UNC13D's overexpression in patients with pancreatic cancer (n = 824) and its prognostic significance and high hazard ratio (HR) in four independent pancreatic cancer cohorts (TCGA, n = 178, p = 0.014, HR = 3.629; ICGC, n = 91, p = 0.000, HR = 4.362; GSE21501, n = 102, p = 0.002, HR = 2.339; GSE28735, n = 45, p = 0.022, HR = 2.681). Additionally, its expression is associated with the clinicopathological progression of pancreatic cancer. Further biological studies have shown that UNC13D regulates the migration of pancreatic cancer cells by coupling the exocytosis of recycling endosomes with focal adhesion turnover via the regulation of FAK phosphorylation. Immunoprecipitation and immunocytochemistry showed the formation of the RAB11-UNC13D-FAK axis in endosomes during integrin recycling. We observed that UNC13D directly interacted with the FERM domain of FAK and regulated FAK phosphorylation in a calcium-dependent manner. Finally, we found co-expression of UNC13D and FAK showed the poorest survival (TCGA, p = 0.000; ICGC, p = 0.036; GSE28735, p = 0.006).We highlight that UNC13D, a novel prognostic factor, promotes pancreatic cancer progression by coupling integrin recycling with focal adhesion turnover via the RAB11-UNC13D-FAK axis for the migration of pancreatic cancer cells.© 2024. The Author(s).