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2018 ; 9
(14
): 11734-11751
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Endogenous CHRNA7-ligand SLURP1 as a potential tumor suppressor and
anti-nicotinic factor in pancreatic cancer
#MMPMID29545933
Throm VM
; Männle D
; Giese T
; Bauer AS
; Gaida MM
; Kopitz J
; Bruckner T
; Plaschke K
; Grekova SP
; Felix K
; Hackert T
; Giese NA
; Strobel O
Oncotarget
2018[Feb]; 9
(14
): 11734-11751
PMID29545933
show ga
Smoking is associated with increased risk and poorer prognosis of pancreatic
ductal adenocarcinoma (PDAC). Nicotine acts through cholinergic nicotinic
receptors, preferentially ?7 (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 CHRNA7(high)-PDAC patients lived longer. In CHRNA7(high) 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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