Abstract：
TGFBR2, a key regulator of the TGFβ signaling pathway, plays a crucial role in gastric cancer (GC) metastasis through its endosomal recycling process. Despite its importance, the mechanisms governing this process remain unclear. Here, we identify integrin β5 (ITGB5) as a critical mediator that promotes TGFBR2 endosomal recycling. Our study reveals elevated expression of ITGB5 in GC, particularly in metastatic cases, correlating with poor patient outcomes. Knockdown of ITGB5 impairs GC cell metastasis both in vitro and in vivo. Mechanistically, ITGB5 facilitates epithelial-mesenchymal transition mediated by TGFβ signaling, thereby enhancing GC metastasis. Acting as a scaffold, ITGB5 interacts with TGFBR2 and SNX17, facilitating SNX17-mediated endosomal recycling of TGFBR2 and preventing lysosomal degradation, thereby maintaining its surface distribution on tumor cells. Notably, TGFβ signaling directly upregulates ITGB5 expression, establishing a positive feedback loop that exacerbates GC metastasis. Our findings shed light on the role of ITGB5 in promoting GC metastasis through SNX17-mediated endosomal recycling of TGFBR2, providing insights for the development of targeted cancer therapies.
摘要：
TGFβ信号通路的关键调节因子TGFBR2,在胃癌(GC)转移过程中起着至关重要的作用。尽管它很重要,管理这一进程的机制仍不清楚。这里,我们确定整合素β5(ITGB5)是促进TGFBR2内体再循环的关键介质.我们的研究揭示了ITGB5在GC中的表达升高，特别是在转移性病例中，与不良患者预后相关。敲除ITGB5在体外和体内都会损害GC细胞转移。机械上,ITGB5促进TGFβ信号介导的上皮间质转化，从而增强GC转移。充当脚手架，ITGB5与TGFBR2和SNX17相互作用，促进SNX17介导的TGFBR2的内体再循环并防止溶酶体降解，从而维持其在肿瘤细胞上的表面分布。值得注意的是,TGFβ信号直接上调ITGB5表达，建立加剧GC转移的正反馈回路。我们的发现揭示了ITGB5在通过SNX17介导的TGFBR2的内体再循环促进GC转移中的作用，为靶向癌症治疗的发展提供了见解。
