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Oncogenic beta-catenin is required for bone morphogenetic protein 4 expression in human cancer cells
Jung-Sik Kim1, Heather Crooks, Tatiana Dracheva
1Department of Oncology, Lombardi Cancer Center, Georgetown University School of Medicine, 3970 Reservoir Road NW, Washington, DC 20007, USA.
Abstract:
Somatic cell gene targeting was used to create an isogenic set of human colon cancer cells that differs only in the presence or absence of their endogenous activated beta-catenin oncogene. Affymetrix Genechip expression profiling of parental cells and gene-targeted derivatives identified numerous novel genes whose expression was dependent on the presence of oncogenic beta-catenin. The transforming growth factor-beta family member bone morphogenetic protein 4 (BMP4), whose receptor is mutated in a rare inherited gastrointestinal cancer predisposition syndrome, was the most highly differentially expressed gene. Additional experiments revealed that the oncogenic allele of beta-catenin specifically is absolutely required for BMP4 expression and secretion by human cancer cells and that BMP4 is overexpressed and secreted by human colon cancer cells with mutant adenomatous polyposis coli genes. These data identify the presence of regulatory interactions between the Wnt and BMP signaling pathways in cancer pathogenesis, providing an intriguing connection between the sporadic and inherited forms of a common human malignancy.
Insights
Researchers discovered that the Wnt and BMP signaling pathways interact in colon cancer development. This finding connects sporadic and inherited forms of this common malignancy, highlighting bone morphogenetic protein 4 (BMP4) as a key player.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Colon cancer is a common malignancy with both sporadic and inherited forms.
- The Wnt signaling pathway, particularly beta-catenin, is frequently activated in colon cancer.
- Bone morphogenetic protein 4 (BMP4) is a transforming growth factor-beta superfamily member implicated in various cellular processes.
Purpose of the Study:
- To investigate the role of oncogenic beta-catenin in gene expression in human colon cancer cells.
- To identify novel genes regulated by activated beta-catenin.
- To explore the relationship between Wnt and BMP signaling in colon cancer pathogenesis.
Main Methods:
- Somatic cell gene targeting to create isogenic colon cancer cell lines with and without activated beta-catenin.
- Affymetrix Genechip expression profiling to compare gene expression patterns.
- Experimental validation of BMP4 expression and secretion in cancer cells.
Main Results:
- Numerous novel genes were identified whose expression is dependent on oncogenic beta-catenin.
- Bone morphogenetic protein 4 (BMP4) was the most highly differentially expressed gene.
- Oncogenic beta-catenin is essential for BMP4 expression and secretion; BMP4 is overexpressed in colon cancer cells with mutant adenomatous polyposis coli genes.
Conclusions:
- Establishes a regulatory interaction between Wnt and BMP signaling pathways in colon cancer.
- Connects sporadic and inherited forms of colon cancer through shared molecular pathways.
- Identifies BMP4 as a key mediator in beta-catenin-driven colon cancer.