Abstract
The CC chemokine receptor 9 (CCR9) and its natural secreted ligand CC motif chemokine ligand 25 (CCL25) have been implicated in cancer metastasis. However, their metastatic potential in non-small cell lung cancer (NSCLC) remains unclear. In the present study, immunohistochemistry was used to detect the expression and localization of CCR9, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-1 and MMP-7 in lung cancer tissue and adjacent normal tissue. The association between the expression of CCR9 and clinical variables was also examined. Reverse transcription-quantitative PCR and western blotting were conducted to detect the expression of VEGF-C, VEGF-D, MMP-1 and MMP-7 in lung cancer cell lines (A549 and SK-MES-1). Migration and invasion assays were conducted to examine cell migration and invasion. Survival and mutation analysis were conducted using published datasets. The expressions of CCR9, VEGF, MMP-1 and MMP-7 were upregulated in cancer tissue, compared with adjacent normal tissue (all P<0.05). Patients with lower expression of CCR9 or CCL25 had better overall survival (OS) compared with those with higher CCR9 or CCL25 expression (P<0.05 and P=0.05, respectively). Furthermore, the expressions of VEGF-C, VEGF-D, MMP-1 and MMP-7 were higher in the CCL25-treated cell lines (all P<0.05), but MMP-7 protein expression was not affected by CCL25 treatment in SK-MES-1 cells (P>0.05). Following treatment with CCL25, lung cancer cells demonstrated higher migratory and invasive potential, which could be blocked by the CCR9 antibody (P<0.05). Survival analysis demonstrated that low expression levels of both CCR9 and CCL25 mRNA indicated favorable OS in patients with NSCLC. Altogether, these results suggested that CCL25 enhanced the phenotype associated with migration and invasion in NSCLC by regulating the expression of VEGF-C, VEGF-D, MMP-1 and MMP-7.