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

Ann Surg Oncol. 2017 Mar;24(3):850-859. doi: 10.1245/s10434-016-5573-9. Epub 2016 Oct 21.


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.

MeSH terms

  • Aged
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • DNA Methylation
  • Databases, Genetic
  • Disease Progression
  • Disease-Free Survival
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Follow-Up Studies
  • Gene Expression
  • Gene Knockdown Techniques
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Male
  • Middle Aged
  • Phenotype
  • Prognosis
  • Promoter Regions, Genetic
  • Signal Transduction / genetics
  • Survival Rate
  • ras Proteins / metabolism
  • rho GTP-Binding Proteins / genetics*
  • rho GTP-Binding Proteins / metabolism*


  • RND1 protein, human
  • ras Proteins
  • rho GTP-Binding Proteins