IQ motif-containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffolding protein that is overexpressed in a number of cancers, including liver cancer, and is associated with protumorigenic processes, such as cell proliferation, motility, and adhesion. IQGAP1 can integrate multiple signaling pathways and could be an effective antitumor target. Therefore, we examined the role of IQGAP1 in tumor initiation and promotion during liver carcinogenesis. We found that ectopic overexpression of IQGAP1 in the liver is not sufficient to initiate tumorigenesis. Moreover, we report that the tumor burden and cell proliferation in the diethylnitrosamine-induced liver carcinogenesis model in Iqgap1^−/− mice may be driven by MET signaling. In contrast, IQGAP1 overexpression enhanced YAP activation and subsequent NUAK2 expression to accelerate and promote hepatocellular carcinoma (HCC) in a clinically relevant model expressing activated (S45Y) β-catenin and MET. Here, increasing IQGAP1 expression in vivo does not alter β-catenin or MET activation; instead, it promotes YAP activity. Overall, we demonstrate that although IQGAP1 expression is not required for HCC development, the gain of IQGAP1 function promotes the rapid onset and increased liver carcinogenesis. Our results show that an adequate amount of IQGAP1 scaffold is necessary to maintain the quiescent status of the liver.

中文翻译：

---

支架蛋白IQGAP1是可有可无的，但其过度表达通过YAP1信号传导促进肝细胞癌


含有 IQ 基序的 GTP 酶激活蛋白 1 (IQGAP1) 是一种普遍表达的支架蛋白，在包括肝癌在内的多种癌症中过度表达，并且与细胞增殖、运动和粘附等促肿瘤过程相关。 IQGAP1可以整合多种信号通路，可能成为有效的抗肿瘤靶点。因此，我们研究了IQGAP1在肝癌发生过程中肿瘤发生和促进中的作用。我们发现肝脏中 IQGAP1 的异位过度表达不足以引发肿瘤发生。此外，我们报告称， Iqgap1 ^-/−小鼠二乙基亚硝胺诱导的肝癌模型中的肿瘤负荷和细胞增殖可能是由 MET 信号驱动的。相比之下，IQGAP1 过表达增强了 YAP 激活和随后的 NUAK2 表达，从而在表达活化 (S45Y) β-catenin 和 MET 的临床相关模型中加速和促进肝细胞癌 (HCC)。在这里，增加体内IQGAP1 表达不会改变 β-catenin 或 MET 激活；相反，它促进了 YAP 活动。总的来说，我们证明虽然 IQGAP1 表达不是 HCC 发展所必需的，但 IQGAP1 功能的获得会促进肝癌的快速发作和增加。我们的结果表明，足够量的 IQGAP1 支架对于维持肝脏的静止状态是必要的。