title: ECT2 regulates the Rho/ERK signalling axis to promote early recurrence in human hepatocellular carcinoma.
abstract: OBJECTIVE
  Early recurrence is the major obstacle for improving the outcome of patients with hepatocellular carcinoma (HCC). Therefore, identifying key molecules contributing to early HCC recurrence can enable the development of novel therapeutic strategies for the clinical management of HCC. Epithelial cell transforming sequence 2 (ECT2) has been implicated in human cancers, but its function in HCC is largely unknown.
  
  
  METHODS
  ECT2 expression was studied by microarrays, immunoblotting and immunohistochemistry in human HCC samples. siRNA- and lentiviral vector-mediated knockdown were employed to decipher the molecular functions of ECT2.
  
  
  RESULTS
  The upregulation of ECT2 is significantly associated with early recurrent HCC disease and poor survival. Knockdown of ECT2 markedly suppressed Rho GTPases activities, enhanced apoptosis, attenuated oncogenicity and reduced the metastatic ability of HCC cells. Moreover, knockdown of ECT2 or Rho also suppressed ERK activation, while the silencing of Rho or ERK led to a marked reduction in cell migration. Stable knockdown of ECT2 in vivo resulted in significant retardation of tumour growth and the suppression of ERK activation. High expression of ECT2 correlates with high ERK phosphorylation and poor survival of HCC patients. Furthermore, ECT2 enhances the expression and stability of RACGAP1, accelerating ECT2-mediated Rho activation to promote metastasis.
  
  
  CONCLUSIONS
  ECT2 is closely associated with the activation of the Rho/ERK signalling axis to promote early HCC recurrence. In addition, ECT2 can crosstalk with RACGAP1 to catalyse the GTP exchange involved in Rho signalling to further regulate tumour initiation and metastasis.
authors.affiliation: Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore, Singapore.
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore, Singapore.
authors.forename: Hongping
authors.initials: H
authors.lastname: Xia
authors.affiliation: Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis Drive Proteos, Singapore, Singapore.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore, Singapore.
authors.forename: Sekar
authors.initials: S
authors.lastname: Karthik
authors.affiliation: Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore, Singapore.
authors.forename: Seshachalam Veerabrahma
authors.initials: SV
authors.lastname: Pratap
authors.affiliation: Division of Surgical Oncology, National Cancer Centre, Singapore 169610, Singapore.
authors.forename: London Lucien
authors.initials: LL
authors.lastname: Ooi
authors.affiliation: Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis Drive Proteos, Singapore, Singapore.
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
authors.affiliation: Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore, Singapore; Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis Drive Proteos, Singapore, Singapore; Cancer & Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: cmrhkm@nccs.com.sg.
authors.forename: Kam M
authors.initials: KM
authors.lastname: Hui
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D020690:GTPase-Activating Proteins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C489850:ECT2 protein, human; D020690:GTPase-Activating Proteins; D011518:Proto-Oncogene Proteins; C115995:mgcRacGAP; D020741:rho GTP-Binding Proteins
keywords: ERK activation; Early recurrence; GTP exchange; Hepatocellular carcinoma (HCC); RACGAP1; Rho GTPases