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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA152309-04
Application #
8517602
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Jhappan, Chamelli
Project Start
2010-09-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$298,934
Indirect Cost
$109,735
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Sun, Hongcheng; Tang, Huamei; Xie, Dacheng et al. (2016) Krüppel-like Factor 4 Blocks Hepatocellular Carcinoma Dedifferentiation and Progression through Activation of Hepatocyte Nuclear Factor-6. Clin Cancer Res 22:502-12
Wei, Daoyan; Wang, Liang; Yan, Yongmin et al. (2016) KLF4 Is Essential for Induction of Cellular Identity Change and Acinar-to-Ductal Reprogramming during Early Pancreatic Carcinogenesis. Cancer Cell 29:324-38
Guo, Kun; Cui, Jiujie; Quan, Ming et al. (2016) A novel KLF4-MSI2 signaling pathway regulates growth and metastasis of pancreatic cancer. Clin Cancer Res :
Zhou, Aidong; Lin, Kangyu; Zhang, Sicong et al. (2016) Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitylation by USP22. Nat Cell Biol 18:954-66
Guo, Junli; Xie, Keping; Zheng, Shaojiang (2016) Molecular Biomarkers of Pancreatic Intraepithelial Neoplasia and Their Implications in Early Diagnosis and Therapeutic Intervention of Pancreatic Cancer. Int J Biol Sci 12:292-301
Cui, J; Xia, T; Xie, D et al. (2016) HGF/Met and FOXM1 form a positive feedback loop and render pancreatic cancer cells resistance to Met inhibition and aggressive phenotypes. Oncogene 35:4708-18
Chen, Yaohui; Li, Yu; Xue, Jianfei et al. (2016) Wnt-induced deubiquitination FoxM1 ensures nucleus β-catenin transactivation. EMBO J 35:668-84
Yan, Yongmin; Li, Zhiwei; Kong, Xiangyu et al. (2016) KLF4-Mediated Suppression of CD44 Signaling Negatively Impacts Pancreatic Cancer Stemness and Metastasis. Cancer Res 76:2419-31
Li, Zhiwei; Guo, Junli; Xie, Keping et al. (2015) Vitamin D receptor signaling and pancreatic cancer cell EMT. Curr Pharm Des 21:1262-7
Xue, Jianfei; Zhou, Aidong; Tan, Christina et al. (2015) Forkhead Box M1 Is Essential for Nuclear Localization of Glioma-associated Oncogene Homolog 1 in Glioblastoma Multiforme Cells by Promoting Importin-7 Expression. J Biol Chem 290:18662-70

Showing the most recent 10 out of 44 publications