Yan Yingcai, Xu Hao, Zhang Linshi, Zhou Xiaohu, Qian Xiaohui, Zhou Jiarong, Huang Yu, Ge Wenhao, Wang Weilin
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China,
Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China,
Onco Targets Ther. 2019 Feb 28;12:1691-1703. doi: 10.2147/OTT.S197844. eCollection 2019.
Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis and limited therapeutic options. Ras-related associated with diabetes (RRAD) belongs to the subfamily of Ras-related GTPases and is associated with several types of cancer, including HCC, although the mechanisms involving RRAD in HCC remains unknown.
We aimed to elucidate the role of RRAD and whether it affects glucose metabolism in HCC by immunohistochemically examining tissue samples from HCC patients and assessing the effect of RRAD overexpression and knockdown on the glucose metabolism, proliferation, cell cycle, and apoptosis of HCC cell lines SK-Hep-1 and Huh7, as well as on tumor progression in vivo.
We demonstrated that RRAD binds to actin gamma 1 (ACTG1). RRAD suppressed aerobic glycolysis in HCC by downregulating ACTG1. On the other hand, ACTG1 promoted HCC proliferation by regulating the cell cycle via downregulation of cyclins and cyclin-dependent kinases and inhibited apoptosis through the mitochondrial apoptosis pathway in vitro. In addition, RRAD retarded tumor growth by downregulating ACTG1 in vivo. ACTG1 was overexpressed in HCC tissues compared with adjacent normal tissues, whereas the expression of RRAD was low in tumor tissues. Low RRAD levels were significantly correlated with large tumor size and advanced tumor stage; high ACTG1 levels were significantly correlated with advanced tumor stage. Furthermore, Kaplan-Meier survival curves showed that HCC patients with high RRAD and low ACTG1 expression may have a better prognosis.
We have shown that RRAD exhibits a tumor-suppressing role in HCC by downregulating glucose metabolism and ACTG1 expression, thus lowering cell proliferation, arresting the cell cycle, and increasing apoptosis. These findings indicate that ACTG1 may act as a downstream effector of RRAD and open a new avenue for potential HCC treatment.
肝细胞癌（HCC）是一种常见的恶性肿瘤，预后较差且治疗选择有限。与糖尿病相关的Ras（RRAD）属于Ras相关GTP酶亚家族，与包括HCC在内的多种癌症相关，尽管RRAD在HCC中的作用机制尚不清楚。
我们旨在通过免疫组织化学检测HCC患者的组织样本，并评估RRAD过表达和敲低对HCC细胞系SK-Hep-1和Huh7的葡萄糖代谢、增殖、细胞周期和凋亡以及体内肿瘤进展的影响，来阐明RRAD的作用以及它是否影响HCC中的葡萄糖代谢。
我们证明RRAD与肌动蛋白γ1（ACTG1）结合。RRAD通过下调ACTG1抑制HCC中的有氧糖酵解。另一方面，ACTG1通过下调细胞周期蛋白和细胞周期蛋白依赖性激酶来调节细胞周期，从而促进HCC增殖，并在体外通过线粒体凋亡途径抑制凋亡。此外，RRAD在体内通过下调ACTG1抑制肿瘤生长。与相邻正常组织相比，ACTG1在HCC组织中过表达，而RRAD在肿瘤组织中的表达较低。RRAD低水平与肿瘤大尺寸和晚期肿瘤分期显著相关；ACTG1高水平与晚期肿瘤分期显著相关。此外，Kaplan-Meier生存曲线显示，RRAD高表达和ACTG1低表达的HCC患者可能预后较好。
我们已经表明，RRAD通过下调葡萄糖代谢和ACTG1表达在HCC中发挥肿瘤抑制作用，从而降低细胞增殖、阻止细胞周期并增加凋亡。这些发现表明ACTG1可能作为RRAD的下游效应物，并为潜在的HCC治疗开辟了一条新途径。
