Gastric cancer (GC) is one of the most common and lethal malignancies worldwide, and its poor prognosis is mainly due to the rapid tumor progression including tumor invasion, distant metastasis, etc. Understanding the molecular mechanisms regulating GC progression lays the basis for the development of targeted therapeutic agents. Increasing evidence suggests that guanine nucleotide-binding protein subunit beta-4 (GNB4), a key subunit of heterotrimeric G protein, plays a crucial role in the initiation and progression of multiple malignancies. However, whether and how GNB4 promotes GC progression are still unknown. In this study, we found that GNB4 was highly expressed in GC tissues compared to that in non-tumor tissues and was significantly associated with tumor invasion depth, pathological stage and poor survival rate of GC patients. Both gain-of-function and loss-of-function studies revealed that GNB4 significantly enhanced GC cell growth and motility both in vitro and in vivo. Further studies revealed that GNB4 overexpression induced G1–S transition and promoted the process of epithelial–mesenchymal transformation. These tumor promoting effects were mediated by GNB4 which activates the Erk1/2 pathway through upregulating Erk1/2 phosphorylation, as U0126, an Erk1/2 phosphorylation inhibitor, could significantly inhibit GNB4-mediated cell proliferation, migration and invasion. In summary, GNB4 contributes to the proliferation and metastasis of GC cells by activating the Erk1/2 signaling pathway, and it may serve as a potential therapeutic target of GC.

中文翻译：

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鸟嘌呤核苷酸结合蛋白亚基β-4通过激活Erk1 / 2促进胃癌的进展。

胃癌（GC）是全球最常见和致命的恶性肿瘤之一，其预后不良主要是由于肿瘤进展迅速，包括肿瘤浸润，远处转移等。了解调节GC进程的分子机制为开发靶向治疗剂奠定了基础。越来越多的证据表明，鸟嘌呤核苷酸结合蛋白亚基β-4（GNB4）是异源三聚体G蛋白的关键亚基，在多种恶性肿瘤的发生和发展中起着至关重要的作用。但是，GNB4是否以及如何促进GC进程仍然未知。在这项研究中，我们发现与非肿瘤组织相比，GNB4在GC组织中高表达，并且与GC患者的肿瘤浸润深度，病理分期和较差的存活率显着相关。功能获得和功能丧失研究均显示，GNB4在体外和体内均显着增强了GC细胞的生长和运动能力。进一步的研究表明，GNB4的过表达诱导了G1–S的转变，并促进了上皮—间质转化的过程。这些肿瘤促进作用是由GNB4介导的，它通过上调Erk1 / 2磷酸化来激活Erk1 / 2途径，因为Erk1 / 2磷酸化抑制剂U0126可以显着抑制GNB4介导的细胞增殖，迁移和侵袭。综上所述，GNB4通过激活Erk1 / 2信号通路促进GC细胞的增殖和转移，并可能作为GC的潜在治疗靶点。