title: Upregulation of Rac GTPase-activating protein 1 is significantly associated with the early recurrence of human hepatocellular carcinoma.
abstract: OBJECTIVE
  To assess the significance of Rac GTPase-activating protein 1 (RACGAP1) expression in identifying HBV-positive human hepatocellular carcinoma (HCC) patients who are at high risk for recurrent disease.
  
  
  METHODS
  The prognostic significance of RACGAP1 was compared with clinicopathologic parameters available at diagnosis using multivariate and log-rank test. RACGAP1 expression and outcome in recurrence was compared between 35 patients with recurrence and 41 patients without recurrence using Kaplan-Meier analysis. RACGAP1-targeted molecules and pathways were identified and characterized by inhibition with siRNA duplexes.
  
  
  RESULTS
  Kaplan-Meier analysis showed that the level of RACGAP1 expression is sufficient to predict the early recurrence of HCC: high RACGAP1 expression correlates with high risk of postresection recurrent HCC (P < 0.0005). Silencing of RACGAP1 in Hep3B and MHCC97-H HCC cells with high endogenous RACGAP1 expression inhibited cell migration and invasion. Using Ingenuity Pathway Analysis, the target molecules silenced in the RACGAP1 interactome were mostly genes related to the mitotic roles of the polo-like kinases. These included PRC1, AURKB, CDC2, ECT2, KIF23, PAK1, and PPP2R5E. In providing clinical corroboration of these results, when expression of these transcripts was analyzed in an expression database that we have established previously for HBV-positive HCC patients, these genes was mostly upregulated in patients who exhibited early recurrent disease and hence provided important corroboration of these results.
  
  
  CONCLUSIONS
  siRNA-silencing RACGAP1 mainly targeted genes in an interactome clinically relevant to early HCC recurrence. Besides being an independent informative prognostic biomarker, RACGAP1 could also be a potential molecular target for designing therapeutic strategies for HCC.
authors.affiliation: Bek Chai Heah Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, Department of Surgical Oncology, National Cancer Centre, Singapore.
authors.forename: Suk Mei
authors.initials: SM
authors.lastname: Wang
authors.forename: London Lucien P J
authors.initials: LL
authors.lastname: Ooi
authors.forename: Kam M
authors.initials: KM
authors.lastname: Hui
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056945:Hep G2 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis*; D011379:Prognosis; D034741:RNA, Small Interfering; D012008:Recurrence; D015398:Signal Transduction; D015854:Up-Regulation / Q000235:genetics*; D020830:rac1 GTP-Binding Protein
chemical_list: D020690:GTPase-Activating Proteins; D034741:RNA, Small Interfering; C115995:mgcRacGAP; D020830:rac1 GTP-Binding Protein