Expression profiles of Nrdc-depleted pancreas
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ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is the devastating disease in urgent need to identify new strategies for diagnosing and treating. Chronic pancreatitis is a risk factor for PDA in humans. Nardilysin (Nrdc, NRDC), a zinc peptidase of the M16 family has been shown to promote cancer cell growth in vitro. Here, we report that pancreatic deletion of Nrdc dramatically accelerates formation of pancreatic intraepithelial neoplasia (PanIN) and invasive PDA in the presence of oncogenic Kras. Nrdc was expressed in the nucleus of pancreatic acinar cells and pancreatic deletion of Nrdc was dispensable for pancreatic development in mice, but led to spontaneous chronic pancreatitis concomitant with acinar-to-ductal conversion, fibrotic change, infiltrated inflammatory cells, increased apoptosis, and atrophic pancreas in adult mice. Ex vivo acinar cell explants culture experiments showed that acinar-to-ductal conversion was not induced through a cell autonomous mechanism and that expression of several chemokines, including Cxcl10, was markedly up-regulated in Nrdc-null pancreatic acinar cells. Microarray analysis revealed that pathways implicated in pancreatitis and tumorigenesis, including chemotaxis, NF-κB and Erk1/2 signaling, were up-regulated in Nrdc-cKO pancreata compared with WT controls. Finally, immunostaining for NRDC revealed absence of NRDC expression in a subset of human PanINs and PDAs. These data demonstrate a previously unappreciated tumor suppressive function of Nrdc in the pancreas through suppressing chronic pancreatitis with acinar-to-ductal conversion in mice.
ORGANISM(S): Mus musculus
PROVIDER: GSE99438 | GEO | 2017/05/31
SECONDARY ACCESSION(S): PRJNA388463
REPOSITORIES: GEO
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