Attenuated RND1 Expression Confers Malignant Phenotype and Predicts Poor Prognosis in Hepatocellular Carcinoma
Attenuated RND1 Expression Confers Malignant Phenotype and Predicts Poor Prognosis in Hepatocellular Carcinoma
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DOI：
10.1245/s10434-016-5573-9
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发表时间：
2017-03-01
影响因子：
3.7
通讯作者：
Mimori, Koshi
中科院分区：
文献类型：
--
作者：
Komatsu, Hisateru;Iguchi, Tomohiro;Mimori, Koshi
RND1基因编码一种属于Rho GT3家族的蛋白质，该蛋白质调节各种细胞功能。RND1表达的缺失激活致癌Ras信号通路。本研究旨在阐明RND 1表达在预测预后中的临床意义，并探讨其在人肝细胞癌（HCC）中的生物学作用。GSE 14520型242例。还进行了基因集富集分析（GSEA）。最后，使用小干扰RNA（siRNA）进行体外敲除实验，在所有队列中，RND1表达随着癌症进展而降低，并且受到启动子甲基化的影响。在我们的HCC病例中，RND1低表达患者的5年总生存率（OS）和无复发生存率明显低于RND1高表达患者。TCGA和GSE 14520分析提供了相似的OS结果。多变量分析表明，在所有三个队列中，RND 1表达是OS的独立预后因素。此外，GSEA显示RND1表达与Ras信号传导活性之间呈负相关。在体外实验中，RND1表达的下调导致肝癌细胞增殖、侵袭和顺铂耐药的显著增加，RND1表达的降低可能通过调节Ras信号通路与肝癌进展相关，并可能作为一种新的临床生物标志物用于预测肝癌患者的预后。
The RND1 gene encodes a protein that belongs to the Rho GTPase family, which regulates various cellular functions. Depletion of RND1 expression activates the oncogenic Ras signaling pathway. In this study, we aimed to clarify the clinical significance of RND1 expression in predicting prognosis and to investigate its biological role in human hepatocellular carcinoma (HCC).The association between RND1 expression and clinical outcomes in patients with HCC was analyzed in three independent cohorts: 120 cases resected in our hospital; 370 cases in The Cancer Genome Atlas (TCGA); and 242 cases in GSE14520. Gene set enrichment analysis (GSEA) was also conducted. Finally, knockdown experiments were performed using small interfering RNA (siRNA) in vitro.In all cohorts, RND1 expression was decreased as cancer progressed, and was affected by promoter methylation. In our HCC cases, the 5-year overall survival (OS) and recurrence-free survival of patients with low RND1 expression was significantly poorer than those of patients with high RND1 expression. TCGA and GSE14520 analyses provided similar results for OS. Multivariate analysis indicated that RND1 expression was an independent prognostic factor for OS in all three cohorts. Additionally, GSEA showed an inverse correlation between RND1 expression and the Ras signaling activity. In vitro, knockdown of RND1 expression resulted in significant increases in proliferation, invasion, and chemoresistance to cisplatin in HCC cells.Reduced RND1 expression in HCC was associated with cancer progression, likely through regulation of the Ras signaling pathway, and may serve as a novel clinical biomarker for predicting prognosis in patients with HCC.