Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death with a mere 9% survival rate. PDACs harbor KRAS (92-95%) and CDKN2A (90%) mutations, overexpress tyrosine kinase receptors, their ligands, and transforming growth factor-? (TGF-β) isoforms. Canonical TGF-β signaling is mediated via Smad2, Smad3 and Smad4, whereas inhibitory Smad6 and Smad7 attenuate TGF-β signaling. Smad7 is overexpressed in PDAC and blocks TGF-β-mediated growth inhibition in vitro. However, the exact role of Smad7 in PDAC is not known. We have established a genetically engineered mouse model of PDAC in which conditional expression of Smad7 and oncogenic KrasG12D are driven in the pancreas by Pdx1-Cre. These LSL-KrasG12D;SMAD7;Pdx1-Cre(KS7C) mice exhibit accelerated progression of pancreatic intraepithelial neoplasia (PanIN) to PDAC by comparison with LSL-KrasG12D;Pdx1-Cre (KC) mice harboring the KrasG12D mutation alone, whereas in the absence of oncogenic Kras, pancreatic histology remains normal in spite of a 9- fold increase in Smad7 mRNA levels. KS7C pancreata exhibit increased PanIN and pancreatic cancer cell proliferation, and these changes are recapitulated in a tetracycline (tet) inducible mouse model of Smad7 (KtetS7C). In both models, pre-neoplastic lesions and PDACs exhibited increased levels of anterior gradient 2 (AGR2), hyper-phosphorylated retinoblastoma protein (p-pRb) and p-Smad2, but low levels of p-Smad3 and p21. Smad7 overexpression in human pancreatic cancer cells (hPCCs) results in downregulated p21 and upregulated AGR2 mRNA and protein levels, and decreased binding of Smad3/4 complex to the AGR2 promoter. Smad3 silencing in hPCCS also resulted in downregulated p21 mRNA and upregulated AGR2 mRNA levels. These findings indicate that Smad7 blocks TGF-β pathways, in part, by preferentially decreasing Smad3 phosphorylation and enhancing AGR2 expression in PDAC, and suggest that targeting Smad7 may constitute a novel therapeutic approach in PDAC.
|Commitee:||Quilliam, Lawrence A., Wek, Ronald C., Xie, Jing Wu|
|School:||Indiana University - Purdue University Indianapolis|
|Department:||Biochemistry and Molecular Biology|
|School Location:||United States -- Indiana|
|Source:||DAI-B 79/02(E), Dissertation Abstracts International|
|Keywords:||Pancreatic cancer, Smad7|
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