PDGF essentially links TGF-beta signaling to nuclear beta-catenin accumulation in hepatocellular carcinoma progression.

  • Fischer A
  • Fuchs E
  • Mikula M
 et al. 
  • 43

    Readers

    Mendeley users who have this article in their library.
  • N/A

    Citations

    Citations of this article.

Abstract

The cooperation of Ras - extracellular signal-regulated kinase/mitogen-activated protein kinase and transforming growth factor (TGF)-beta signaling provokes an epithelial to mesenchymal transition (EMT) of differentiated p19(ARF) null hepatocytes, which is accompanied by a shift in malignancy and gain of metastatic properties. Upon EMT, TGF-beta induces the secretion and autocrine regulation of platelet-derived growth factor (PDGF) by upregulation of PDGF-A and both PDGF receptors. Here, we demonstrate by loss-of-function analyses that PDGF provides adhesive and migratory properties in vitro as well as proliferative stimuli during tumor formation. PDGF signaling resulted in the activation of phosphatidylinositol-3 kinase, and furthermore associated with nuclear beta-catenin accumulation upon EMT. Hepatocytes expressing constitutively active beta-catenin or its negative regulator Axin were employed to study the impact of nuclear beta-catenin. Unexpectedly, active beta-catenin failed to accelerate proliferation during tumor formation, but in contrast, correlated with growth arrest. Nuclear localization of beta-catenin was accompanied by strong expression of the Cdk inhibitor p16(INK4A) and the concomitant induction of the beta-catenin target genes cyclin D1 and c-myc. In addition, active beta-catenin revealed protection of malignant hepatocytes against anoikis, which provides a prerequisite for the dissemination of carcinoma. From these data, we conclude that TGF-beta acts tumor progressive by induction of PDGF signaling and subsequent activation of beta-catenin, which endows a subpopulation of neoplastic hepatocytes with features of cancer stem cells..

Author-supplied keywords

  • b -catenin
  • epithelial to mesenchymal transi-
  • hepatocyte
  • pdgf
  • tgf- b
  • tion

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document

Authors

  • a N M Fischer

  • E Fuchs

  • M Mikula

  • H Huber

  • H Beug

  • W Mikulits

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free