Invasive pancreatic cancer (PDA) is a lethal disease. While certain genetic and epigenetic alterations have been well known for years, to date this has not resulted in useful preventive and/or therapeutic modalities. Our research goal is to identify driving alterations in gene expression that can be utilized to develop effective strategie to control PDA differentiation and progression. Our previous studies have demonstrated that transcription factor KLF4 is drastically decreased in invasive PDA and this dysregulation critically promotes PDA biology, whereas PanINs do not exhibit substantially reduced KLF4 expression. In sharp contrast, our recent study has shown a consistent miR-152 underexpression/DNMT1 overexpression in invasive PDA as compared to that in PanINs. Causally linking miR-152-DNMT1-KLF4 pathway to PDA differentiation/dedifferentiation is highly significant in understanding PDA progression. We postulate that downregulation of miR-152 expression causes DNMT1 overexpression and KLF4 downregulation and consequential acquisition of de-differentiated phenotype in PDA, i.e., a switch from PanINs to invasive PDA. Therefore, activation and/or restoration of miR-152 signaling could attenuate PanINs progression. To test our hypothesis, we propose three specific aims: (1) To determine the clinical significance of PDA differentiation and its regulation by KLF4 hypermethylation; (2) To determine the causal role of DNMT1 in PDA differentiation and potential mechanisms underlying its dysregulation; and (3) Determine the utility of targeting miR-152-DNMT1-KLF4 signaling pathway for therapeutic intervention of PDA. These three novel specific aims with clinical relevant questions, mechanistic substantiation using clinical materials and translational validation, 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. Our proposed studies will take advantage of the unique resources available at MD Anderson, including our large collection of PDA specimens and mouse models. Given the important role of miR-152/DNMT1/KLF4 we will uncover, we predict that completion of these studies will provide insightful information for the molecular genetic basis of PDA progression and for identification of molecular targets to design effective intervention strategies. In the long term, our study also ca lead to further investigation of the molecular mechanisms mediating dysregulation of this novel miR-152/DNMT1/KLF4 signaling pathway, and potential translation or our findings into developing effective preventive and therapeutic strategies to control PDA progression.
Tumor differentiation dictates the disease outcome. This proposal is designed to determine the epigenetic mechanisms that drive PDA de-differentiation with a focus on the causal role of altered miR-152/DNMT1/KLF4 signaling pathway. This novel and significant area of research would help better understand PDA progression and identify molecular targets for effective interventions.
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