Systematic name M1373
Brief description Genes up-regulated in MMH-RT cells (hepatocytes displaying an invasive, metastatic phenotype) during epithelial to mesenchymal transition (EMT).
Full description or abstract Polarized hepatocytes expressing hyperactive Ha-Ras adopt an invasive and metastatic phenotype in cooperation with transforming growth factor (TGF)-beta. This dramatic increase in malignancy is displayed by an epithelial to mesenchymal transition (EMT), which mimics the TGF-beta-mediated progression of human hepatocellular carcinomas. In culture, hepatocellular EMT occurs highly synchronously, facilitating the analysis of molecular events underlying the various stages of this process. Here, we show that in response to TGF-beta, phosphorylated Smads rapidly translocated into the nucleus and activated transcription of target genes such as E-cadherin repressors of the Snail superfamily, causing loss of cell adhesion. Within the TGF-beta superfamily of cytokines, TGF-beta1, -beta2 and -beta3 were specific for the induction of hepatocellular EMT. Expression profiling of EMT kinetics revealed 78 up- and 235 downregulated genes, which preferentially modulate metabolic activities, extracellular matrix composition, transcriptional activities and cell survival. Independent of the genetic background, platelet-derived growth factor (PDGF)-A ligand and both PDGF receptor subunits were highly elevated, together with autocrine secretion of bioactive PDGF. Interference with PDGF signalling by employing hepatocytes expressing the dominant-negative PDGF-alpha receptor revealed decreased TGF-beta-induced migration in vitro and efficient suppression of tumour growth in vivo. In conclusion, these results provide evidence for a crucial role of PDGF in TGF-beta-mediated tumour progression of hepatocytes and suggest PDGF as a target for therapeutic intervention in liver cancer.
Collection C2: curated gene sets
      CGP: chemical and genetic perturbations
Source publication Pubmed 16607286   Authors: Gotzmann J,Fischer AN,Zojer M,Mikula M,Proell V,Huber H,Jechlinger M,Waerner T,Weith A,Beug H,Mikulits W
Exact source Fig 4, 5: red
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(show 7 gene sets from the same authors)
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Organism Mus musculus
Contributed by Jessica Robertson (MSigDB Team)
Source platform AFFY_Mu11K
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Version history 3.1: First introduced

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