BCL9 Promotes Tumor Progression by Conferring Enhanced Proliferative, Metastatic, and Angiogenic Properties to Cancer Cells
| Autor: | Monica M. Bertagnolli, Daniel E. Carrasco, Yunyu Zhang, Sanford D. Markowitz, Lois Myeroff, Moshe E. Gatt, Mala Mani, Daniel R. Carrasco, Hiroshi Ikeda, Kohichi Takada, Jui Dutta-Simmons, Kenneth C. Anderson, Felipe Diaz-Griffero, Victor Pena-Cruz |
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| Rok vydání: | 2009 |
| Předmět: |
Vascular Endothelial Growth Factor A
Cancer Research Angiogenesis Cell Growth Processes medicine.disease_cause Article Cell Movement Cell Line Tumor medicine Humans RNA Messenger Neoplasm Metastasis Neovascularization Pathologic Oncogene biology CD44 Wnt signaling pathway LRP5 Neoplasm Proteins Wnt Proteins Hyaluronan Receptors Oncology Tumor progression Colonic Neoplasms Cancer cell Disease Progression biology.protein Cancer research Multiple Myeloma Carcinogenesis Transcription Factors |
| Zdroj: | Cancer Research. 69:7577-7586 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-09-0773 |
| Popis: | Several components of the Wnt signaling cascade have been shown to function either as tumor suppressor proteins or as oncogenes in multiple human cancers, underscoring the relevance of this pathway in oncogenesis and the need for further investigation of Wnt signaling components as potential targets for cancer therapy. Here, using expression profiling analysis as well as in vitro and in vivo functional studies, we show that the Wnt pathway component BCL9 is a novel oncogene that is aberrantly expressed in human multiple myeloma as well as colon carcinoma. We show that BCL9 enhances β-catenin–mediated transcriptional activity regardless of the mutational status of the Wnt signaling components and increases cell proliferation, migration, invasion, and the metastatic potential of tumor cells by promoting loss of epithelial and gain of mesenchymal-like phenotype. Most importantly, BCL9 knockdown significantly increased the survival of xenograft mouse models of cancer by reducing tumor load, metastasis, and host angiogenesis through down-regulation of c-Myc, cyclin D1, CD44, and vascular endothelial growth factor expression by tumor cells. Together, these findings suggest that deregulation of BCL9 is an important contributing factor to tumor progression. The pleiotropic roles of BCL9 reported in this study underscore its value as a drug target for therapeutic intervention in several malignancies associated with aberrant Wnt signaling. [Cancer Res 2009;69(19):7577–86] |
| Databáze: | OpenAIRE |
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