A common genetic variation of melanoma inhibitory activity-2 labels a subtype of pancreatic adenocarcinoma with high endoplasmic reticulum stress levels

Bo Kong; Weiwei Wu; Nataliya Valkovska; Carsten Jäger; Xin Hong; Ulrich Nitsche; Helmut Friess; Irene Esposito; Mert Erkan; Jörg Kleeff; Christoph W Michalski

doi:10.1038/srep08109

A common genetic variation of melanoma inhibitory activity-2 labels a subtype of pancreatic adenocarcinoma with high endoplasmic reticulum stress levels

Sci Rep. 2015 Feb 6:5:8109. doi: 10.1038/srep08109.

Authors

Affiliations

¹ Department of Surgery, Technische Universität München, Munich, Germany.
² Institute of Pathology, Technische Universität München, Munich, Germany.
³ Department of Surgery, Koc School of Medicine, Istanbul, Turkey.
⁴ Department of Surgery, University of Heidelberg, Germany.

Abstract

HNF1 homeobox A (HNF1A)-mediated gene expression constitutes an essential component of the secretory pathway in the exocrine pancreas. Melanoma inhibitory activity 2 (MIA2), a protein facilitating protein secretion, is an HNF1A target. Protein secretion is precisely coordinated by the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) system. Here, we demonstrate that HNFA and MIA2 are expressed in a subset of human PDAC tissues and that HNF1A induced MIA2 in vitro. We identified a common germline variant of MIA2 (c.A617G: p.I141M) associated with a secretory defect of the MIA2 protein in PDAC cells. Patients carrying MIA2(I141M) survived longer after tumor resection but the survival benefit was restricted to those patients who received adjuvant chemotherapy. The MIA2(I141M) variant was associated with high expression of ER stress/UPR genes--in particular those of the ERN1/XBP arm--in human PDAC samples. Accordingly, PDAC cell lines expressing the MIA2(I141M) variant expressed high levels of ERN1 and were more sensitive to gemcitabine. These findings define an interaction between the common MIA2(I141M) variant and the ER stress/UPR system and specify a subgroup of PDAC patients who are more likely to benefit from adjuvant chemotherapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / drug therapy
Adenocarcinoma / genetics*
Adenocarcinoma / metabolism*
Adenocarcinoma / mortality
Antigens, Neoplasm
Antimetabolites, Antineoplastic / pharmacology
Carcinoma, Pancreatic Ductal / drug therapy
Carcinoma, Pancreatic Ductal / genetics
Carcinoma, Pancreatic Ductal / metabolism
Carcinoma, Pancreatic Ductal / mortality
Chemotherapy, Adjuvant
Deoxycytidine / analogs & derivatives
Deoxycytidine / pharmacology
Drug Resistance, Neoplasm / genetics
Endoplasmic Reticulum Stress*
Endoribonucleases / genetics
Endoribonucleases / metabolism
Gemcitabine
Gene Expression
Genetic Variation*
Hepatocyte Nuclear Factor 1-alpha / genetics
Humans
Neoplasm Proteins
Pancreatic Neoplasms / drug therapy
Pancreatic Neoplasms / genetics*
Pancreatic Neoplasms / metabolism*
Pancreatic Neoplasms / mortality
Prognosis
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Treatment Outcome
Tumor Suppressor Proteins / genetics*

Substances

Antigens, Neoplasm
Antimetabolites, Antineoplastic
Hepatocyte Nuclear Factor 1-alpha
MIA2 protein, human
Neoplasm Proteins
Tumor Suppressor Proteins
Deoxycytidine
ERN1 protein, human
Protein Serine-Threonine Kinases
Endoribonucleases
Gemcitabine