title: Attenuated RND1 Expression Confers Malignant Phenotype and Predicts Poor Prognosis in Hepatocellular Carcinoma.
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.
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.|Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors: Hisateru
authors: H
authors: Komatsu
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors: Tomohiro
authors: T
authors: Iguchi
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors: Takaaki
authors: T
authors: Masuda
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors: Hidenari
authors: H
authors: Hirata
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.|Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors: Masami
authors: M
authors: Ueda
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.|Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors: Shinya
authors: S
authors: Kidogami
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors: Yushi
authors: Y
authors: Ogawa
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors: Kuniaki
authors: K
authors: Sato
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors: Qingjiang
authors: Q
authors: Hu
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors: Sho
authors: S
authors: Nambara
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors: Tomoko
authors: T
authors: Saito
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors: Shotaro
authors: S
authors: Sakimura
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors: Ryutaro
authors: R
authors: Uchi
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors: Shuhei
authors: S
authors: Ito
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors: Hidetoshi
authors: H
authors: Eguchi
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
authors: Keishi
authors: K
authors: Sugimachi
authors: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors: Hidetoshi
authors: H
authors: Eguchi
authors: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors: Yuichiro
authors: Y
authors: Doki
authors: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan.
authors: Masaki
authors: M
authors: Mori
authors: Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan. kmimori@beppu.kyushu-u.ac.jp.
authors: Koshi
authors: K
authors: Mimori
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D019175:DNA Methylation; D030541:Databases, Genetic; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000235:genetics; D015996:Survival Rate; D018631:ras Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C491772:RND1 protein, human; D018631:ras Proteins; D020741:rho GTP-Binding Proteins