Transforming growth factor-β-induced plasticity causes a migratory stemness phenotype in hepatocellular carcinoma

Andrea Malfettone, Jitka Soukupova, Esther Bertran, Eva Crosas-Molist, Raquel Lastra, Joan Fernando, Petra Koudelkova, Bhavna Rani, Ángels Fabra, Teresa Serrano, Emilio Ramos, Wolfgang Mikulits, Gianluigi Giannelli, Isabel Fabregat

Research output: Contribution to journalArticle

Abstract

As part of its potential pro-tumorigenic actions, Transforming Growth Factor-(TGF)-β induces epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) cells. Whether EMT induces changes in tumor cell plasticity has not been fully explored yet. Here, we analyze the effects of TGF-β on the EMT and stem-related properties of HCC cells and the potential correlation among those processes. The translational aim of the study was to propose a TGF-β/EMT/stem gene signature that would help in recognizing HCC patients as good candidates for anti-TGF-β therapy. Results indicate that when TGF-β induces EMT in HCC cells, a switch in the expression of stem genes is observed and their stemness potential and migratory/invasive capacity are enhanced. However, TGF-β may induce a partial EMT in some epithelial HCC cells, increasing the expression of mesenchymal genes and CD44, but maintaining epithelial gene expression. Epithelial cells show higher stemness potential than the mesenchymal ones, but respond to TGF-β increasing their migratory and invasive capacity. In HCC patient samples, TGFB1 expression most frequently correlates with a partial EMT, increase in mesenchymal genes and CD44 expression, as well as maintenance or over-expression of epithelial-related genes.

Original languageEnglish
Pages (from-to)39-50
Number of pages12
JournalCancer Letters
Volume392
DOIs
Publication statusPublished - Apr 28 2017

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Keywords

  • Antigens, CD44
  • Carcinoma, Hepatocellular
  • Cell Line, Tumor
  • Cell Movement
  • Cell Plasticity
  • Epithelial Cells
  • Epithelial-Mesenchymal Transition
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Liver Neoplasms
  • Mesenchymal Stromal Cells
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells
  • Phenotype
  • Protein-Serine-Threonine Kinases
  • RNA Interference
  • Receptors, Transforming Growth Factor beta
  • Signal Transduction
  • Time Factors
  • Transcriptome
  • Transfection
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Comparative Study
  • Journal Article

Cite this

Malfettone, A., Soukupova, J., Bertran, E., Crosas-Molist, E., Lastra, R., Fernando, J., Koudelkova, P., Rani, B., Fabra, Á., Serrano, T., Ramos, E., Mikulits, W., Giannelli, G., & Fabregat, I. (2017). Transforming growth factor-β-induced plasticity causes a migratory stemness phenotype in hepatocellular carcinoma. Cancer Letters, 392, 39-50. https://doi.org/10.1016/j.canlet.2017.01.037