ILEI requires oncogenic Ras for the epithelial to mesenchymal transition of hepatocytes and liver carcinoma progression.
In human hepatocellular carcinoma (HCC), epithelial to mesenchymal transition (EMT) correlates with aggressiveness of tumors and poor survival. We employed a model of EMT based on immortalized p19(ARF) null hepatocytes (MIM), which display tumor growth upon expression of oncogenic Ras and undergo EMT through the synergism of Ras and transforming growth factor (TGF)-beta. Here, we show that the interleukin-related protein interleukin-like EMT inducer (ILEI), a novel EMT-, tumor- and metastasis-inducing protein, cooperates with oncogenic Ras to cause TGF-beta-independent EMT. Ras-transformed MIM hepatocytes overexpressing ILEI showed cytoplasmic E-cadherin, loss of ZO-1 and induction of alpha-smooth muscle actin as well as platelet-derived growth factor (PDGF)/PDGF-R isoforms. As shown by dominant-negative PDGF-R expression in these cells, ILEI-induced PDGF signaling was required for enhanced cell migration, nuclear accumulation of beta-catenin, nuclear pY-Stat3 and accelerated growth of lung metastases. In MIM hepatocytes expressing the Ras mutant V12-C40, ILEI collaborated with PI3K signaling resulting in tumor formation without EMT. Clinically, human HCC samples showed granular or cytoplasmic localization of ILEI correlating with well and poorly differentiated tumors, respectively. In conclusion, these data indicate that ILEI requires cooperation with oncogenic Ras to govern hepatocellular EMT through mechanisms involving PDGF-R/beta-catenin and PDGF-R/Stat3 signaling.
Lahsnig
C
C
Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Borschke-Gasse 8a, Vienna, Austria.
Mikula
M
M
Petz
M
M
Zulehner
G
G
Schneller
D
D
van Zijl
F
F
Huber
H
H
Csiszar
A
A
Beug
H
H
Mikulits
W
W
D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D011905:Genes, ras / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology; D051176:beta Catenin / Q000502:physiology
D016207:Cytokines; C488587:Fam3c protein, mouse; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D017479:Receptors, Platelet-Derived Growth Factor