Format

Send to

Choose Destination
Gut. 2014 Jun;63(6):984-95. doi: 10.1136/gutjnl-2013-305221. Epub 2013 Sep 11.

Genetic inactivation of Nupr1 acts as a dominant suppressor event in a two-hit model of pancreatic carcinogenesis.

Author information

1
Centre de Recherche en Carcérologie de Marseille (CRCM), INSERM UMR 1068, CNRS UMR 7258, Aix-Marseille University and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, , Marseille, France.

Abstract

BACKGROUND:

Nuclear protein 1 (Nupr1) is a major factor in the cell stress response required for Kras(G12D)-driven formation of pancreatic intraepithelial neoplastic lesions (PanINs). We evaluated the relevance of Nupr1 in the development of pancreatic cancer.

METHODS:

We investigated the role of Nupr1 in pancreatic ductal adenocarcinoma (PDAC) progression beyond PanINs in Pdx1-cre;LSL-Kras(G12D);Ink4a/Arf(fl/fl)(KIC) mice.

RESULTS:

Even in the context of the second tumorigenic hit of Ink4a/Arf deletion, Nupr1 deficiency led to suppression of malignant transformation involving caspase 3 activation in premalignant cells of KIC pancreas. Only half of Nupr1-deficient;KIC mice achieved PDAC development, and incident cases survived longer than Nupr1(wt);KIC mice. This was associated with the development of well-differentiated PDACs in Nupr1-deficient;KIC mice, which displayed enrichment of genes characteristic of the recently identified human classical PDAC subtype. Nupr1-deficient;KIC PDACs also shared with human classical PDACs the overexpression of the Kras-activation gene signature. In contrast, Nupr1(wt);KIC mice developed invasive PDACs with enriched gene signature of human quasi-mesenchymal (QM) PDACs. Cells derived from Nupr1-deficient;KIC PDACs growth in an anchorage-independent manner in vitro had higher aldehyde dehydrogenase activity and overexpressed nanog, Oct-4 and Sox2 transcripts compared with Nupr1(wt);KIC cells. Moreover, Nupr1-deficient and Nurpr1(wt);KIC cells differed in their sensitivity to the nucleoside analogues Ly101-4b and WJQ63. Together, these findings show the pivotal role of Nupr1 in both the initiation and late stages of PDAC in vivo, with a potential impact on PDAC cell stemness.

CONCLUSIONS:

According to Nupr1 status, KIC mice develop tumours that phenocopy human classical or QM-PDAC, respectively, and present differential drug sensitivity, thus becoming attractive models for preclinical drug trials.

KEYWORDS:

CANCER; ONCOGENES; PANCREAS; PANCREATIC CANCER; STRESS

PMID:
24026351
DOI:
10.1136/gutjnl-2013-305221
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center