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)-b. 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-b-independent EMT. Ras-transformed MIM hepatocytes overexpressing ILEI showed cytoplasmic E-cadherin, loss of ZO-1 and induction of a-smooth muscle actin as well as plateletderived 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 b-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/b-catenin and PDGF-R/ Stat3 signaling.
*Anthrax Toxin Receptor 1 (ANTXR1; also known as Tumor Endothelial Marker 8, TEM8) is one of several genes that was recently found to be up-regulated in tumor-associated endothelial cells. In vitro, the protein can link extracellular matrix components with the actin cytoskeleton to promote cell adhesion and cell spreading. Both, ANTXR1 and the closely related ANTXR2 can bind anthrax toxin and interact with lipoprotein receptor-related protein 5 and 6, which also work as coreceptors in the WNT signaling pathway. Here, we report the cloning of chick ANTXR1 from a suppression subtractive hybridization screen for fibroblast growth factor (FGF) -inducible genes in chicken embryonic facial mesenchyme. We show that chicken ANTXR1 is dynamically expressed throughout embryogenesis, starting from Hamburger and Hamilton stage 10. Furthermore, we demonstrate that FGF signaling is sufficient, but not necessary, to induce ANTXR1 expression in chicken facial mesenchyme. Developmental Dynamics 239:680-687,
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