J Pathol: 广医三院发现胃癌侵袭转移新机制

    最近国际顶尖级病理学期刊《Journal of Pathology》发表了广州医科大学附属第三医院中心实验室/暨南大学晏光荣课题组的最新研究成果。该研究发现了调控胃癌侵袭转移新的基因和作用机制，找到了胃癌新的预后标记物。

    来自广州医科大学附属第三医院和暨南大学的研究人员，在国际顶尖的病理学学术期刊《Journal of Pathology》发表胃癌侵袭转移最新成果。发现了调控胃癌侵袭转移新基因及其作用机制，获得了胃癌新的预后标记物。广州医科大学附属第三医院晏光荣教授和陈德教授是这篇论文的共同通讯作者。本课题得到国家自然科学基金、广东省科技计划项目和广州番禺区科技计划项目的资助。

    我国作为胃癌的高发国家，全球每年胃癌新发病例中，42%的新发病例数来自我国，数量近40万人。在世界上位居肿瘤发病率第4位、死亡率第2位。往往远端转移是胃癌致死的关键原因。研究团队发现ACK1在胃癌组织中表达显著上调，这种上调与胃癌的临床预后差密切相关。进一步发现ACK1可以通过诱导EMT促使胃癌的侵袭转移。采用SILAC定量蛋白质组学技术筛选发现ACK1主要通过调控新基因ECD而促使胃癌的侵袭转移。其主要作用机制是，ACK1通过激活AKT信号通路调控转录因子POU2F1的水平而上调ECD基因的转录。此信号通路的激活，可以作为胃癌临床预后判断的重要标记，也可以作为抗癌药物干预的潜在靶标。

    原文链接：ACK1 promotes gastric cancer epithelial-mesenchymal transition and metastasis through AKT-POU2F1-ECD signaling

Amplification of the activated Cdc42-associated kinase 1 (ACK1) gene is frequent in gastric cancer (GC). However, little is known about the clinical roles and molecular mechanisms of ACK1 abnormalities in GC. Here, we found that the ACK1 protein level and ACK1 phosphorylation at Tyr 284 were frequently elevated in GC and associated with poor patient survival. Ectopic ACK1 expression in GC cells induced epithelial-mesenchymal transition (EMT) and promoted migration and invasion in vitro, and metastasis in vivo; the depletion of ACK1 induced the opposite effects. We utilized SILAC quantitative proteomics to discover that the level of the cell cycle-related protein ecdysoneless homologue (ECD) was markedly altered by ACK1. Overexpression of ECD promoted EMT, migration, and invasion in GC, similar to the effects of ACK1 overexpression. Silencing of ECD completely blocked the augmentation of ACK1 overexpression-induced EMT, migration, and invasion. Mechanistically, ACK1 phosphorylated AKT at Thr 308 and Ser 473 and activated the AKT pathway to up-regulate the transcription factor POU2F1, which directly bound to the promoter region of its novel target gene ECD and thus regulated ECD expression in GC cells. Furthermore, the phosphorylation levels of AKT at Thr 308 and Ser 473 and POU2F1 and ECD levels were positively associated with ACK1 levels in clinical GC specimens. Collectively, we have demonstrated that ACK1 promotes EMT, migration, and invasion by activating AKT-POU2F1-ECD signalling in GC cells. ACK1 may be employed as a new prognostic factor and therapeutic target for GC.