title: Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma.
abstract: OBJECTIVE
  How hepatocellular carcinoma (HCC) cells acquire the ability to invade surrounding tissue is unknown, but epithelial mesenchymal transition (EMT) likely plays a role. We investigate how transforming growth factor (TGF)-beta1 and extracellular matrix protein Laminin-5 (Ln-5) induce EMT and cancer invasion.
  
  
  METHODS
  Snail, Slug, E-cadherin, beta-catenin and Ln-5 were investigated on HCC tissues and on HCC cell lines.
  
  
  RESULTS
  We show that in HCC but not in peritumoral tissue of the same HCC patients, Ln-5, Snail, and Slug are up-regulated, E-cadherin is down-regulated and beta-catenin is translocated into the nuclei. In vitro, HCC "invasive" cells, partially EMT-transformed, show low levels of E-cadherin. In presence of Ln-5, Snail, and Slug are up-regulated, E-cadherin is down-regulated, beta-catenin is translocated into the nuclei, and cells undergo a dramatic morphological change, becoming scattered and undergoing a complete EMT. This effect is reversed by anti-alpha3 but not by anti-alpha6 integrin blocking antibody. HCC "noninvasive" cells are not EMT-transformed, and have constitutively high levels of E-cadherin. In presence of Ln-5, cells undergo partial EMT, Snail, and Slug are up-regulated, E-cadherin is down-regulated but cells do not scatter. However, the presence of both Ln-5 and TGF-beta1 completes the EMT process, beta-catenin is translocated into the nuclei, cells scatter and become invasive, recalling the "invasive" cells. In this case, too, the effect is reversed by anti-alpha3 integrin blocking antibody.
  
  
  CONCLUSIONS
  Our study shows that Ln-5 and TGF-beta1 cooperatively induce EMT in HCC, suggesting the microenvironment as a potential target for new biological therapies.
authors.affiliation: Department of Internal Medicine, Immunology, and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Bari, Italy. g.giannelli@intmed.uniba.it
authors.forename: G
authors.initials: G
authors.lastname: Giannelli
authors.forename: C
authors.initials: C
authors.lastname: Bergamini
authors.forename: E
authors.initials: E
authors.lastname: Fransvea
authors.forename: C
authors.initials: C
authors.lastname: Sgarra
authors.forename: S
authors.initials: S
authors.lastname: Antonaci
mesh_terms: D015820:Cadherins / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000503:physiopathology* / Q000556:secondary; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008648:Mesoderm / Q000473:pathology*; D009361:Neoplasm Invasiveness; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D051176:beta Catenin / Q000235:genetics; D000097794:Kalinin
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D000097794:Kalinin; C000604407:SNAI1 protein, human; C508960:TGFB1 protein, human