Dissertation/Thesis Abstract

The author has requested that access to this graduate work be delayed until 2019-10-02. After this date, this graduate work will be available on an open access basis.
Elucidating the Role of Smad7 in Pancreatic Cancer Through In Vivo Studies
by Savant, Sudha, Ph.D., Indiana University - Purdue University Indianapolis, 2017, 196; 10623365
Abstract (Summary)

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.

Indexing (document details)
Advisor: Korc, Murray
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
Source Type: DISSERTATION
Subjects: Biochemistry, Oncology
Keywords: Pancreatic cancer, Smad7
Publication Number: 10623365
ISBN: 9780355361360