Our recent studies have shown that increased KLF4 protein expression suppressed the growth of human pancreatic cancer, whereas knockdown of KLF4 expression did the opposite. Moreover, we have identified three KLF4 alternative splice variants and a point-mutant KLF4 in human pancreatic cancer cells. Experimentally enforced expression of one of the splice variant, KLF41, promoted tumor growth. However, the underlying mechanisms for the impact of altered KLF4 expression and function on pancreatic cancer pathogenesis are unclear. We postulate that genetic and epigenetic changes of KLF4 impact its tumor suppressor function and contribute to pancreatic cancer pathogenesis. To test our hypothesis, we propose the following three specific aims.
Specific Aim 1 will test the hypothesis that genetic and epigenetic alterations lead to altered KLF4 expression and function and affect pancreatic cancer clinical outcome. Genetic (mutation and LOH) and epigenetic (promoter hypermethylation and alternative splicing) changes of KLF4 and their clinical significance in pancreatic cancer pathogenesis will be determined.
Specific aim 2 will test the hypothesis that aberrant KLF4 expression and function promotes tumor growth and metastasis. Impacts of altered KLF4 expression and function on the malignant phenotype with a focus on angiogenic phenotype of human pancreatic cancer cells will be determine using in vitro and animal models.
Specific Aim 3 will test the hypothesis that altered KLF4 expression and function results in dysregulated Sp1 expression and the imbalanced expression and function of Sp1 and KLF4 leads to an increased expression of pro-angiogenic factors that are predominantly regulated by Sp1. Impacts of altered expression and function of KLF4 on the expression and function of Sp1 and its downstream molecules in human pancreatic cancer cells will be determined. These three specific aims are supported by our respective preliminary data and can be tested independently using our unique research resources, yet they are highly interrelated and support one another. We predict that completion of these studies will provide insightful information for the molecular genetic basis of pancreatic cancer pathogenesis and for identification of molecular targets to design effective therapeutic strategies. In the long term, our study also can lead to further investigation of the molecular mechanisms mediating disregulated KLF4 expression and function.

Public Health Relevance

KLF4 is a newly identified putative tumor suppressor in gastrointestinal cancers. However, the critical role of KLF4 signaling in human cancer development and progression in general and human pancreatic cancer in particular is unclear.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129956-05
Application #
8329655
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Ault, Grace S
Project Start
2008-09-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$247,971
Indirect Cost
$86,951
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
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Li, Zhiwei; Jia, Zhiliang; Gao, Yong et al. (2015) Activation of vitamin D receptor signaling downregulates the expression of nuclear FOXM1 protein and suppresses pancreatic cancer cell stemness. Clin Cancer Res 21:844-53

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