title: EDIL3 is a novel regulator of epithelial-mesenchymal transition controlling early recurrence of hepatocellular carcinoma.
abstract: OBJECTIVE
  Patients with advanced hepatocellular carcinoma (HCC) continue to have a dismal prognosis. Early recurrence, metastases and angiogenesis are the major obstacles to improve the outcome of HCC. Epithelial-mesenchymal transition (EMT) is a key contributor to cancer metastasis and recurrence, which are the major obstacles to improve prognosis of HCC.
  
  
  METHODS
  Combining gene expression profiles of HCC samples with or without early recurrence and established cell lines with epithelial or mesenchymal phenotype, EDIL3 was identified as a novel regulator of EMT. The expression of EDIL3 was evaluated by quantitative PCR, Western blotting or immunohistochemistry. The effects of EDIL3 on the angiogenesis and metastasis of HCC cells were examined by wound healing, Matrigel invasion and tube formation assay in vitro and orthotopic xenograft mouse model of HCC in vivo. The signaling pathways of EDIL3 mediated were investigated through microarray and Western blotting analysis.
  
  
  RESULTS
  EDIL3 was identified as a novel regulator of EMT, which contributes to angiogenesis, metastasis and recurrence of HCC. EDIL3 induces EMT and promotes HCC migration, invasion and angiogenesis in vitro. Mechanistically, overexpression of EDIL3, which was regulated by the downregulation of miR-137 in HCC, triggered the activation of ERK and TGF-β signaling through interactions with αvβ3 integrin. Blocking ERK and TGF-β signaling overcomes EDIL3 induced angiogenesis and invasion. Using the orthotopic xenograft mouse model of HCC, we demonstrated that EDIL3 enhanced the tumorigenic, metastatic and angiogenesis potential of HCC in vivo.
  
  
  CONCLUSIONS
  EDIL3-mediated activation of TGF-β and ERK signaling could provide therapeutic implications for HCC.
authors.affiliation: Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
authors.forename: Hongping
authors.initials: H
authors.lastname: Xia
authors.affiliation: Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510060, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510060, PR China.
authors.forename: Hengjun
authors.initials: H
authors.lastname: Gao
authors.affiliation: Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
authors.forename: Karthik
authors.initials: K
authors.lastname: Sekar
authors.affiliation: Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
authors.forename: Veerabrahma Pratap
authors.initials: VP
authors.lastname: Seshachalam
authors.affiliation: Department of Surgical Oncology, National Cancer Centre, Singapore; Department of General Surgery, Singapore General Hospital, Singapore.
authors.forename: London Lucien P J
authors.initials: LL
authors.lastname: Ooi
authors.affiliation: Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis Drive Proteos, Singapore. Electronic address: cmrhkm@nccs.com.sg.
authors.forename: Kam M
authors.initials: KM
authors.lastname: Hui
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D015815:Cell Adhesion Molecules; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000235:genetics*; D013997:Time Factors
chemical_list: D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; C491706:Edil3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D012334:RNA, Neoplasm
keywords: EDIL3; ERK; Epithelial-mesenchymal transition; Hepatocellular carcinoma; TGF-β; Tumour angiogenesis