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Attenuated RND1 Expression Confers Malignant Phenotype and Predicts Poor Prognosis in Hepatocellular Carcinoma

Hisateru Komatsu MD, Tomohiro Iguchi MD, PhD, Takaaki Masuda MD, PhD, Hidenari Hirata MD, Masami Ueda MD, Shinya Kidogami MD, Yushi Ogawa MD, Kuniaki Sato MD, Qingjiang Hu MD, Sho Nambara MD, Tomoko Saito MD, Shotaro Sakimura MD, Ryutaro Uchi MD, Shuhei Ito MD, PhD, Hidetoshi Eguchi MD, PhD, Keishi Sugimachi MD, PhD, Hidetoshi Eguchi MD, PhD, Yuichiro Doki MD, PhD, Masaki Mori MD, PhD, Koshi Mimor
Translational Research and Biomarkers
Volume 24, Issue 3 / March , 2017

ABSTRACT

Background

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).

Methods

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.

Results

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.

Conclusions

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.

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