The long-term objective for this proposal is the elucidation of molecular mechanisms for the wingless-type (Wnt)/beta-catenin signaling pathway in malignant mesothelioma (MM) and the development of molecular therapies for this malignancy. Mesothelioma is a relatively uncommon but inexorably fatal tumor, affecting about 3000 new patients in the United States annually. Despite advances in cancer treatment, the medium survival rate remains low and most patients die within two years after diagnosis. The pathogenesis of mesothelioma remains poorly understood and the molecular mechanism by which mesothelial cells undergo neoplastic transformation is largely unknown. For this proposal, we will test the hypothesis that aberrant activation of Wnt signaling pathway plays important roles in malignant mesothelioma. Preliminary data from our laboratory showed that the Wnt signaling pathway is activated in MM as evidenced by increased cytosolic/nuclear beta-catenin, and c-Myc, the two downstream target genes, downregulation of the potential endogenous inhibitor secreted frizzled related protein (SFRP2), and an increased phosphorylation of the Wnt pathway mediator dishevelled protein (Dvl-3). These observations have not been described previously nor elucidated in MM.
The specific Aims for this application are 1) to confirm that Wnt signaling pathway is activated in mesothelioma in a large number of primary tumor samples: 2) to investigate molecular mechanisms of Wnt signaling activation in mesothelioma. initially by examining the role of SFRP2 and Dvl-3; 3) to investigate whether a Wnt-1 signaling is a survival factor, thus inhibits apoptosis, in mesothelioma using an anti-Wnt-1 ligand monoclonal antibody and siRNA; and 4) to develop molecular therapies by targeting the Wnt-1 ligand with monoclonal antibody in vivo. Recent information about the Wnt signaling pathway reveals its vital importance in both embryogenesis and oncogenesis. Our study aims to reveals its role in malignant mesothelioma, and to add significantly to the emerging knowledge about the Wnt pathway in cancer in general.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA093708-03
Application #
7217464
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Yassin, Rihab R,
Project Start
2005-03-01
Project End
2009-02-28
Budget Start
2007-03-15
Budget End
2008-02-29
Support Year
3
Fiscal Year
2007
Total Cost
$216,193
Indirect Cost
Name
University of California San Francisco
Department
Surgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Hung, Ming-Szu; Mao, Jian-Hua; Xu, Zhidong et al. (2011) Cul4A is an oncogene in malignant pleural mesothelioma. J Cell Mol Med 15:350-8
Kratz, Johannes R; Yagui-Beltran, Adam; Jablons, David M (2010) Cancer stem cells in lung tumorigenesis. Ann Thorac Surg 89:S2090-5
Gao, Zhi; Xu, Zhidong; Hung, Ming-Szu et al. (2009) Promoter demethylation of WIF-1 by epigallocatechin-3-gallate in lung cancer cells. Anticancer Res 29:2025-30
Gao, Zhi; Xu, Zhidong; Hung, Ming-Szu et al. (2009) Procaine and procainamide inhibit the Wnt canonical pathway by promoter demethylation of WIF-1 in lung cancer cells. Oncol Rep 22:1479-84
Hung, Ming-Szu; Xu, Zhidong; Lin, Yu-Ching et al. (2009) Identification of hematein as a novel inhibitor of protein kinase CK2 from a natural product library. BMC Cancer 9:135
Yagui-Beltran, Adam; M Jablons, David (2009) A translational approach to lung cancer research: From EGFRs to Wnt and cancer stem cells. Ann Thorac Cardiovasc Surg 15:213-20
Clement, Genevieve; Guilleret, Isabelle; He, Biao et al. (2008) Epigenetic alteration of the Wnt inhibitory factor-1 promoter occurs early in the carcinogenesis of Barrett's esophagus. Cancer Sci 99:46-53
Okamoto, Junichi; Mikami, Iwao; Tominaga, Yuichi et al. (2008) Inhibition of Hsp90 leads to cell cycle arrest and apoptosis in human malignant pleural mesothelioma. J Thorac Oncol 3:1089-95
You, Liang; Xu, Zhidong; Punchihewa, Chandanamali et al. (2008) Evaluation of a chemical library of small-molecule Dishevelled antagonists that suppress tumor growth by down-regulating T-cell factor-mediated transcription. Mol Cancer Ther 7:1633-8
Yagui-Beltran, Adam; He, Biao; Jablons, David M (2008) The role of cancer stem cells in neoplasia of the lung: past, present and future. Clin Transl Oncol 10:719-25

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