Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma

Gastroenterology. 2005 Nov;129(5):1375-83. doi: 10.1053/j.gastro.2005.09.055.

Abstract

Background & aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / physiopathology*
  • Carcinoma, Hepatocellular / secondary
  • Cell Adhesion Molecules / genetics*
  • Cell Adhesion Molecules / metabolism
  • Epithelial Cells / pathology*
  • Epithelial Cells / physiology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Liver Neoplasms / physiopathology*
  • Mesoderm / pathology*
  • Neoplasm Invasiveness
  • Snail Family Transcription Factors
  • Transcription Factors / genetics
  • Transforming Growth Factor beta / genetics*
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta1
  • beta Catenin / genetics

Substances

  • Cadherins
  • Cell Adhesion Molecules
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • TGFB1 protein, human
  • Transcription Factors
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • beta Catenin
  • kalinin