Wnt11 signaling promotes proliferation, transformation, and migration of IEC6 intestinal epithelial cells.
Wnts are morphogens with well recognized functions during embryogenesis. Aberrant Wnt signaling has been demonstrated to be important in colorectal carcinogenesis. However, the role of Wnt in regulating normal intestinal epithelial cell proliferation is not well established. Here we determine that Wnt11 is expressed throughout the mouse intestinal tract including the epithelial cells. Conditioned media from Wnt11-secreting cells stimulated proliferation and migration of IEC6 intestinal epithelial cells. Co-culture of Wnt11-secreting cells with IEC6 cells resulted in morphological transformation of the latter as evidenced by the formation of foci, a condition also accomplished by stable transfection of IEC6 with a Wnt11-expressing construct. Treatment of IEC6 cells with Wnt11 conditioned media failed to induce nuclear translocation of beta-catenin but led to increased activities of protein kinase C and Ca(2+)/calmodulin-dependent protein kinase II. Inhibition of protein kinase C resulted in a decreased ability of Wnt11 to induce foci formation in IEC6 cells. Finally, E-cadherin was redistributed in Wnt11-treated IEC6 cells, resulting in diminished E-cadherin-mediated cell-cell contact. We conclude that Wnt11 stimulates proliferation, migration, cytoskeletal rearrangement, and contact-independent growth of IEC6 cells by a beta-catenin-independent mechanism. These findings may help understand the molecular mechanisms that regulate proliferation and migration of intestinal epithelial cells.
Ouko
Lillian
L
Divisions of Digestive Diseases and Endocrinology, Department of Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Ziegler
Thomas R
TR
Gu
Li H
LH
Eisenberg
Leonard M
LM
Yang
Vincent W
VW
D021581:Active Transport, Cell Nucleus; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D018938:Caco-2 Cells; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000166:cytology*; D008156:Luciferases / Q000378:metabolism; D008856:Microscopy, Fluorescence; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D014018:Tissue Distribution; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D051153:Wnt Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495268:Ctnnb1 protein, rat; D017077:Culture Media, Conditioned; D003598:Cytoskeletal Proteins; D006023:Glycoproteins; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; D008156:Luciferases; D011493:Protein Kinase C