CXCR2 in non-small cell lung cancer (NSCLC) has been studied mainly in stromal 
cells and is known to increase tumor inflammation and angiogenesis. Here, we 
examined the prognostic importance of CXCR2 in NSCLC and the role of CXCR2 and 
its ligands in lung cancer cells. The effect of CXCR2 expression on tumor cells 
was studied using stable knockdown clones derived from a murine KRAS/p53-mutant 
lung adenocarcinoma cell line with high metastatic potential and an orthotopic 
syngeneic mouse model and in vitro using a CXCR2 small-molecule antagonist 
(SB225002). CXCR2 protein expression was analyzed in tumor cells from 262 NSCLC. 
Gene expression profiles for CXCR2 and its ligands (CXCR2 axis) were analyzed in 
52 human NSCLC cell lines and 442 human lung adenocarcinomas. Methylation of 
CXCR2 axis promoters was determined in 70 human NSCLC cell lines. Invasion and 
metastasis were decreased in CXCR2 knockdown clones in vitro and in vivo. 
SB225002 decreased invasion in vitro. In lung adenocarcinomas, CXCR2 expression 
in tumor cells was associated with smoking and poor prognosis. CXCR2 axis gene 
expression profiles in human NSCLC cell lines and lung adenocarcinomas defined a 
cluster driven by CXCL5 and associated with smoking, poor prognosis, and RAS 
pathway activation. Expression of CXCL5 was regulated by promoter methylation. 
The CXCR2 axis may be an important target in smoking-related lung 
adenocarcinoma.