RRAD suppresses the Warburg effect by downregulating ACTG1 in hepatocellular carcinoma
RRAD suppresses the Warburg effect by downregulating ACTG1 in hepatocellular carcinoma
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RRAD 通过下调肝细胞癌中的 ACTG1 抑制 Warburg 效应
DOI：
10.2147/ott.s197844
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发表时间：
2019-01-01
影响因子：
4
通讯作者：
Wang, Weilin
中科院分区：
文献类型：
--
作者：
Yan, Yingcai;Xu, Hao;Wang, Weilin
目的：肝细胞癌（HCC）是一种常见的恶性肿瘤，预后较差，治疗选择有限。 Ras 相关糖尿病 (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 中的作用机制仍不清楚。 患者和方法：我们旨在通过免疫组织化学检查 HCC 患者的组织样本并评估 RRAD 过表达和敲低对糖代谢、增殖、细胞周期和代谢的影响，阐明 RRAD 的作用以及它是否影响 HCC 中的葡萄糖代谢。 HCC 细胞系 SK-Hep-1 和 Huh7 的凋亡，以及体内肿瘤进展。结果：我们证明 RRAD 与肌动蛋白 gamma 1 (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，促进HCC增殖，并在体外通过线粒体凋亡途径抑制细胞凋亡。此外，RRAD 通过下调体内 ACTG1 来延缓肿瘤生长。与癌旁正常组织相比，ACTG1在HCC组织中过表达，而RRAD在肿瘤组织中表达较低。低 RRAD 水平与大肿瘤大小和晚期肿瘤分期显着相关；高ACTG1水平与晚期肿瘤分期显着相关。此外，Kaplan-Meier生存曲线显示，高RRAD和低ACTG1表达的HCC患者可能有更好的预后。结论：我们发现RRAD通过下调糖代谢和ACTG1表达，从而降低细胞增殖、阻滞细胞周期和增加细胞凋亡，在HCC中发挥肿瘤抑制作用。这些发现表明 ACTG1 可能作为 RRAD 的下游效应器，并为潜在的 HCC 治疗开辟了新途径。
Purpose: 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.Patients and methods: 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.Results: 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.Conclusion: 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.