Metastatic pancreatic cancer is a lethal disease. The genetic and epigenetic alterations and consequent changes in molecular signaling behind pancreatic cancer development and progression remain unclear. Functional identification and validation of progression biomarkers is essential for pancreatic cancer diagnosis and treatment. Recent studies indicated that the aberrant Wnt/?-catenin pathway activation in pancreatic cancer cells play an important role in cell proliferation, invasion, and metastasis. Stability and nuclear translocation of ?-catenin protein is a critical step leading to malignant phenotype of pancreatic cancer. Our recent studies also have shown that transcription factor FoxM1 critically contributes to cell proliferation, invasion and tumorigenicity of human pancreatic cancer. Importantly, our studies have shown that FoxM1 and ?-catenin appears to be associated with each other physically and functionally in pancreatic cancer cells. The prior studies including our own are sufficient to make us believe that the interactions between FoxM1 and ?-catenin signaling play a critical role in pancreatic cancer development and progression. To test our hypothesis, we have designed several sets of experiments organized around three specific aims with well-defined goals.
Aim 1 will determine whether FoxM1 interacts with ?-catenin and promotes its nuclear translocation;
Aim 2 will define the role of the interaction of ?-catenin/FoxM1 in pancreatic tumor invasion and metastasis;
and Aim 3 will to determine the expression of ?-catenin and FoxM1 in pancreatic cancer tissues and delineate their clinical significance in human pancreatic cancer pathogenesis. Thus, our studies integrate three levels of functional validating investigation: molecular biology, cell biology, and clinicohistopathology. Completion of our proposed studies will represents a substantial advance in our understanding the in-depth mechanism of dysregulated ?-catenin and FoxM1 expression and function in general and in pancreatic cancer development and progression in particular. Thus, our proposed studies are fundamentally important to understand the interaction between ?-catenin signaling and FoxM1 signaling and its function impact on pancreatic cancer biology and to determine its value as a molecular target for designing effective modality to control pancreatic cancer cell growth, invasion and metastasis. In the long term, our study also can lead to further investigation of the molecular mechanisms mediating disregulated Wnt/?-Catenin signaling and its crosstalk with FoxM1pathway. Translation of our findings into clinical patient care is another long-term goal of ours.

Public Health Relevance

Crosstalk between ?-catenin and FoxM1 signaling pathways and its impact on progressive growth and invasion of pancreatic cancer cells is unknown and our appealing evidence reveals a novel and significant research area of pancreatic cancer development and progression. Our studies integrate three levels of functional validating investigation: molecular biology, cell biology, and clinicohistopathology.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Jhappan, Chamelli
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University of Texas MD Anderson Cancer Center
Internal Medicine/Medicine
Other Domestic Higher Education
United States
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Li, Lei; Li, Zhaoshen; Kong, Xiangyu et al. (2014) Down-regulation of microRNA-494 via loss of SMAD4 increases FOXM1 and ?-catenin signaling in pancreatic ductal adenocarcinoma cells. Gastroenterology 147:485-97.e18
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Cui, Jiujie; Shi, Min; Xie, Dacheng et al. (2014) FOXM1 promotes the warburg effect and pancreatic cancer progression via transactivation of LDHA expression. Clin Cancer Res 20:2595-606
Huang, Chen; Du, Jiawei; Xie, Keping (2014) FOXM1 and its oncogenic signaling in pancreatic cancer pathogenesis. Biochim Biophys Acta 1845:104-16
Xue, Jianfei; Lin, Xia; Chiu, Wen-Tai et al. (2014) Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-?-dependent cancer metastasis. J Clin Invest 124:564-79
Huang, Chen; Xie, Dacheng; Cui, Jiujie et al. (2014) FOXM1c promotes pancreatic cancer epithelial-to-mesenchymal transition and metastasis via upregulation of expression of the urokinase plasminogen activator system. Clin Cancer Res 20:1477-88
Huang, Chen; Xie, Keping (2013) Analysis of the potential for pancreatic cancer metastasis in vitro and in vivo. Methods Mol Biol 980:301-19
Kong, Xiangyu; Li, Lei; Li, Zhaoshen et al. (2013) Dysregulated expression of FOXM1 isoforms drives progression of pancreatic cancer. Cancer Res 73:3987-96
Shi, Min; Cui, Jiujie; Xie, Keping (2013) Signaling of miRNAs-FOXM1 in cancer and potential targeted therapy. Curr Drug Targets 14:1192-202

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