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[Cancer Research 63, 4547-4551, August 1, 2003]
© 2003 American Association for Cancer Research

Molecular Biology and Genetics

Wnt Pathway Activation in Mesothelioma

Evidence of Dishevelled Overexpression and Transcriptional Activity of ß-Catenin1

Kazutsugu Uematsu, Satoshi Kanazawa, Liang You, Biao He, Zhidong Xu, Kai Li, B. Matija Peterlin, Frank McCormick and David M. Jablons2

Thoracic Oncology Laboratory [K. U., L. Y., B. H., Z. X., K. L., F. M., D. M. J.], Department of Medicine [S. K., B. M. P.], University of California, San Francisco Cancer Center, San Francisco, California 94115, and The Fourth Department of Internal Medicine, Nippon Medical School, Tokyo 113-8602, Japan [K. U.]

Malignant pleural mesothelioma is a relatively uncommon and yet incurable tumor. The pathogenesis of mesothelioma remains poorly understood. This study evaluated the role of Wnt signaling in mesothelioma. Western blot analysis was conducted to confirm the expression of Dishevelled (Dvl) and cytosolic ß-catenin in matched autologous tissue samples (tumor and normal pleura), malignant pleural effusions, and in established mesothelioma cell lines LRK1A, REN and H513. Thirteen of 15 mesotheliomas examined showed consistent overexpression of Dvl and increased cytosolic ß-catenin levels as compared with controls. To evaluate T-cell factor (Tcf)-dependent transcriptional activity of ß-catenin, luciferase assays were conducted. Fresh mesothelioma cells (effusion derived), as well as LRK1A, REN, and H513 cell lines showed a significant fold increase (1.5–2.4-fold, P < 0.01) in Tcf-dependent transcriptional activity of ß-catenin. To evaluate the biological significance of Dvl function in mesothelioma, a PDZ domain deletion mutant ({Delta}PDZ-Dvl) was created and stably transfected into LRK1A, REN, and H513. The effect of {Delta}PDZ-Dvl on mesothelioma growth was assayed in vitro (colony formation assay in soft agar) and in vivo (s.c. implantation in athymic mice NCRNU-M). In mesothelioma cells tested, {Delta}PDZ-Dvl-mediated inhibition of Dvl decreased cytosolic ß-catenin levels, diminished Tcf-mediated transcription, and suppressed tumorigenesis of LRK1A and REN in vitro and in vivo. {Delta}PDZ-Dvl also down-regulated expression of c-myc in REN and COX-2 in H513. Our data suggest that in malignant pleural mesothelioma, Wnt signaling is activated through Dvl overexpression and downstream signaling through ß-catenin. Inhibition of this signaling leads to significant antitumor effects. These results demonstrate Dvl overexpression in human cancer and, specifically, that Wnt signaling plays a role in mesothelioma pathogenesis. These data offer possible new avenues for therapeutic intervention.




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Copyright © 2003 by the American Association for Cancer Research.