ER stress protein AGR2 precedes and is involved in the regulation of pancreatic cancer initiation

The mechanisms of initiation of pancreatic ductal adenocarcinoma (PDAC) are still largely unknown. In the present study, we analysed the role of anterior gradient-2 (AGR2) in the earliest stages of pancreatic neoplasia. Immunohistochemical analysis of chronic pancreatitis (CP) and peritumoral areas...

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Published in:	Oncogene Vol. 36; no. 22; pp. 3094 - 3103
Main Authors:	Dumartin, L, Alrawashdeh, W, Trabulo, S M, Radon, T P, Steiger, K, Feakins, R M, di Magliano, M P, Heeschen, C, Esposito, I, Lemoine, N R, Crnogorac-Jurcevic, T
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-06-2017 Nature Publishing Group
Subjects:	13/105 13/106 13/51 631/67/1504/1713 64/60 Animals Apoptosis Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - metabolism Carcinoma, Pancreatic Ductal - pathology Cell Biology Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - metabolism Cell Transformation, Neoplastic - pathology Disease Models, Animal Endoplasmic reticulum Endoplasmic Reticulum Chaperone BiP Endoplasmic Reticulum Stress - physiology Heat shock proteins Human Genetics Humans Internal Medicine Medicine Medicine & Public Health Mice Mucoproteins - biosynthesis Mucoproteins - deficiency Mucoproteins - genetics Mucoproteins - metabolism Oncogene Proteins Oncology Original original-article Pancreatic cancer Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Proto-Oncogene Proteins p21(ras) - genetics Proto-Oncogene Proteins p21(ras) - metabolism
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Summary:	The mechanisms of initiation of pancreatic ductal adenocarcinoma (PDAC) are still largely unknown. In the present study, we analysed the role of anterior gradient-2 (AGR2) in the earliest stages of pancreatic neoplasia. Immunohistochemical analysis of chronic pancreatitis (CP) and peritumoral areas in PDAC tissues showed that AGR2 was present in tubular complexes (TC) and early pancreatic intraepithelial neoplasia (PanINs). Moreover, AGR2 was also found in discrete subpopulations of non-transformed cells neighbouring these pre-neoplastic lesions. In primary cells derived from human patient-derived xenograft (PDX) model, flow-cytometry revealed that AGR2 was overexpressed in pancreatic cancer stem cells (CSC) compared with non-stem cancer cells. In LSL-Kras G12D ; Pdx1-Cre ( KC ) mouse model Agr2 induction preceded the formation of pre-neoplastic lesions and their development was largely inhibited by Agr2 deletion in engineered LSL-Kras G12D ; Pdx1-Cre ; Agr2 −/− mice. In vitro , AGR2 expression was stimulated by tunicamycin-induced endoplasmic reticulum (ER) stress in both KRAS wild-type normal pancreas cells, as well as in KRAS mutated pancreatic cancer cells and was essential for ER homoeostasis. The unfolded protein response proteins GRP78, ATF6 and XBP1s were found expressed in CP and PDAC peritumoral tissues, but in contrast to AGR2, their expression was switched off during TC and PanIN formation. Real-time PCR and ELISA analyses showed that ER stress induced a pro-inflammatory phenotype in pancreatic normal, cancer and stellate cells. Moreover, AGR2 expression was inducible by paracrine transfer of ER stress and pro-inflammation between different pancreatic cell types. Our findings demonstrate that AGR2 induced in ER-stressed and inflammatory pre-neoplastic pancreas is a potential marker of cancer progenitor cells with an important functional role in PDAC initiation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2016.459