Involvement of the Wnt-β-catenin pathway in invasion and migration of oral squamous carcinoma cells.
The Wnt/β-catenin pathway plays a critical role in cell proliferation and oncogenesis. To clarify the role of cytoplasmic accumulation of β-catenin in oral squamous cell carcinoma (SCC), the cDNA of a mutant form of β-catenin that lacks the entire region with the glycogen synthase kinase-3 β (GSK-3β)-specific phosphorylation site was transfected into Ca9-22 cells whose β-catenin had been expressed predominantly at the membrane, and permanent cell lines expressing aberrant β-catenin in the cytoplasm and nucleus were produced. These transfectants, C1 and C5, proliferated at similar rates to the parental Ca9-22 cells, but the cell morphology changed from polygonal to spindle-shaped and close cell-cell interaction was lost. These mutant β-catenin-expressing cells exhibited a significantly higher invasion/migration capacity than wild-type Ca9-22 cells. The transcriptional activities of this mutant β-catenin form was enhanced in these cells which could be demonstrated by an elevated level of the transcription factor T-cell factor (Tcf)/lymphoid enhancer factor (Lef)-dependent reporter gene activity as well as by the up-regulation of Wnt/β-catenin target gene matrix metalloproteinase (MMP)-7. Moreover, we observed the redistribution of E-cadherin, the rearrangement of actin filaments, and the elevation of active Rho family members, Cdc42 and Rac. These results suggest that aberrant cytoplasmic accumulation of β-catenin can induce Tcf/Lef-mediated transcriptional activity, up-regulate MMP-7, and induce epithelial and mesenchymal transition (EMT). This would enhance the invasion and migration of oral SCC cells.
Iwai
Soichi
S
Department of Oral and Maxillofacial Surgery II, Osaka University Graduated School of Dentistry, Suita, Osaka 565-0871, Japan. s-iwai@dent.osaka-u.ac.jp
Yonekawa
Atsuko
A
Harada
Chie
C
Hamada
Masakazu
M
Katagiri
Wataru
W
Nakazawa
Mituhiro
M
Yura
Yoshiaki
Y
D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000096:biosynthesis / Q000235:genetics; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis / Q000235:genetics; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
C495270:CTNNB1 protein, human; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D051153:Wnt Proteins; D051176:beta Catenin; D020783:Matrix Metalloproteinase 7