Komatsu Hisateru, Iguchi Tomohiro, Masuda Takaaki, Hirata Hidenari, Ueda Masami, Kidogami Shinya, Ogawa Yushi, Sato Kuniaki, Hu Qingjiang, Nambara Sho, Saito Tomoko, Sakimura Shotaro, Uchi Ryutaro, Ito Shuhei, Eguchi Hidetoshi, Sugimachi Keishi, Eguchi Hidetoshi, Doki Yuichiro, Mori Masaki, Mimori Koshi
Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
Ann Surg Oncol. 2017 Mar;24(3):850-859. doi: 10.1245/s10434-016-5573-9. Epub 2016 Oct 21.
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.
RND1基因编码一种属于Rho GTPase家族的蛋白质，该家族调节多种细胞功能。RND1表达的缺失会激活致癌的Ras信号通路。在本研究中，我们旨在阐明RND1表达在预测预后方面的临床意义，并研究其在人类肝细胞癌（HCC）中的生物学作用。
在三个独立队列中分析了RND1表达与HCC患者临床结局之间的关联：我院切除的120例病例；癌症基因组图谱（TCGA）中的370例病例；以及GSE14520中的242例病例。还进行了基因集富集分析（GSEA）。最后，在体外使用小干扰RNA（siRNA）进行了敲低实验。
在所有队列中，RND1表达随着癌症进展而降低，并受启动子甲基化影响。在我们的HCC病例中，RND1表达低的患者的5年总生存期（OS）和无复发生存期明显低于RND1表达高的患者。TCGA和GSE14520分析对OS得出了相似结果。多变量分析表明，RND1表达是所有三个队列中OS的独立预后因素。此外，GSEA显示RND1表达与Ras信号活性呈负相关。在体外，RND1表达的敲低导致HCC细胞的增殖、侵袭和对顺铂的化疗耐药性显著增加。
HCC中RND1表达降低与癌症进展相关，可能是通过调节Ras信号通路，并且可能作为预测HCC患者预后的一种新的临床生物标志物。
