Oncotarget

Research Papers:

Endogenous CHRNA7-ligand SLURP1 as a potential tumor suppressor and anti-nicotinic factor in pancreatic cancer

Verena M. Throm _, David Männle, Thomas Giese, Andrea S. Bauer, Matthias M. Gaida, Juergen Kopitz, Thomas Bruckner, Konstanze Plaschke, Svetlana P. Grekova, Klaus Felix, Thilo Hackert, Nathalia A. Giese and Oliver Strobel

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Oncotarget. 2018; 9:11734-11751. https://doi.org/10.18632/oncotarget.24312

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Abstract

Verena M. Throm1, David Männle1, Thomas Giese2, Andrea S. Bauer3, Matthias M. Gaida4, Juergen Kopitz4, Thomas Bruckner5, Konstanze Plaschke1, Svetlana P. Grekova1, Klaus Felix1, Thilo Hackert1, Nathalia A. Giese1 and Oliver Strobel1

1European Pancreas Centre/EPZ, Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany

2Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany

3Department of Functional Genomics, DKFZ, Heidelberg, Germany

4Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

5Institute of Medical Biometry and Informatics/IMBI, University Hospital Heidelberg, Heidelberg, Germany

Correspondence to:

Nathalia A. Giese, email: nathalia.giese@med.uni-heidelberg.de

Keywords: SLURP1; CHRNA7; pancreatic cancer; nicotine

Received: March 13, 2017     Accepted: December 05, 2017     Published: January 24, 2018

ABSTRACT

Smoking is associated with increased risk and poorer prognosis of pancreatic ductal adenocarcinoma (PDAC). Nicotine acts through cholinergic nicotinic receptors, preferentially α7 (CHRNA7) that also binds the endogenous ligand SLURP1 (Secreted Ly-6/uPAR-Related Protein 1). The clinical significance of SLURP1 and its interaction with nicotine in PDAC are unclear. We detected similar levels of SLURP1 in sera from healthy donors and patients with chronic pancreatitis or PDAC; higher preoperative values were associated with significantly better survival in patients with resected tumors. Pancreatic tissue was not a source of circulating SLURP1 but contained diverse CHRNA7-expressing cells, preferentially epithelial and immune, whereas stromal stellate cells and a quarter of the tumor cells lacked CHRNA7. The CHRNA7 mRNA levels were decreased in PDAC, and CHRNA7high-PDAC patients lived longer. In CHRNA7high COLO357 and PANC-1 cultures, opposing activities of SLURP1 (anti-malignant/CHRNA7-dependent) and nicotine (pro-malignant/CHRNA7-infidel) were exerted without reciprocally interfering with receptor binding or downstream signaling. These data suggested that the ligands act independently and abolish each other’s effects through a mechanism resembling functional antagonism. Thus, SLURP1 might represent an inborn anti-PDAC defense being sensitive to and counteracting nicotine. Boosting SLURP1-CHRNA7 interaction might represent a novel strategy for treatment in high-risk individuals, i.e., smokers with pancreatic cancer.


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