Clinicopathological and prognostic significance of interleukin-8 expression and its relationship to KRAS mutation in lung adenocarcinoma

Abstract

Background: On the basis of our recent findings of oncogenic KRAS-induced interleukin-8 (IL-8) overexpression in non-small cell lung cancer, we assessed the clinicopathological and prognostic significances of IL-8 expression and its relationship to KRAS mutations in lung adenocarcinomas.

Methods: IL-8 expression was examined by quantitative RT-PCR using 136 of surgical specimens from lung adenocarcinoma patients. The association between IL-8 expression, clinicopathological features, KRAS or EGFR mutation status and survival was analysed.

Results: IL-8 was highly expressed in tumours from elderly patients or smokers and in tumours with pleural involvement or vascular invasion. In a non-smokers' subgroup, IL-8 level positively correlated with age. IL-8 was highly expressed in tumours with KRAS mutations compared with those with EGFR mutations or wild-type EGFR/KRAS. Lung adenocarcinoma patients with high IL-8 showed significantly shorter disease-free survival (DFS) and overall survival (OS) than those with low IL8. DFS and OS were significantly shorter in the patients with mutant KRAS/high IL-8 than in those with wild-type KRAS/low IL-8. Cox regression analyses demonstrated that elevated IL-8 expression correlated with unfavourable prognosis.

Conclusions: Our findings suggest that IL-8 expression is associated with certain clinicopathological features including age and is a potent prognostic marker in lung adenocarcinoma, especially in oncogenic KRAS-driven adenocarcinoma.

Figure 1

IL-8 mRNA expression in 136 surgical specimens from lung adenocarcinoma patients. (A) Comparisons of IL-8 expression between patients who were ⩾70 years old and those who were <70 years old; between males and females; between smokers and non-smokers; and between patients with different pathological tumour stages. (B) Comparisons of IL-8 expression between patients who were ⩾70 years old and those who were <70 years old in the smoker subgroup and the non-smoker subgroup. (C) Correlations between IL-8 expression and age in smokers and non-smokers. (D) Comparisons of IL-8 expression between tumours with or without pleural involvement; tumours with or without lymphatic permeation; and tumours with or without vascular invasion. (E) Differential IL-8 expression among the three groups that were classified according to KRAS and EGFR mutation status. (F) Comparisons of IL-8 expression between ⩾70-year-old patients and <70-year-old patients in the KRAS-mutants, EGFR-mutants and wild-type EGFR/KRAS subgroups. (G) Correlations between IL-8 expression and age in the KRAS-mutant, EGFR-mutant and wild-type EGFR/KRAS subgroups. (H) Significant correlations between IL-8 expression and age in non-smokers with KRAS mutations and non-smokers with EGFR mutations. (I) Comparisons of IL-8 expression between smokers and non-smokers in the KRAS-mutant, EGFR-mutant and wild-type EGFR/KRAS subgroups. IL-8 expression levels were determined by quantitative RT–PCR analysis and normalised to the mean values (=1 a.u.) from 10 non-cancerous lung tissue samples. The points represent the mean IL-8 levels obtained from four independent experiments. Differences between two groups were tested with the Mann–Whitney test, and differences between three or more groups were tested with the Kruskal–Wallis test.

Figure 2

(A) Correlations between IL-8 expression and CD34 score in lung adenocarcinomas. Grey squares: EGFR-mutants; red triangles: KRAS-mutants; black circles: tumours with wild-type EGFR/KRAS. Comparisons of CD34 score between lung adenocarcinomas with high IL-8 expression and those with low IL-8 expression (cut-off point: the median IL-8 level) in (B) the whole group or (C) the KRAS-mutants subgroup.

Figure 3

Kaplan–Meier analysis of (A) disease-free survival (DFS) and (B) overall survival (OS) in 119 lung adenocarcinoma patients who had not received EGFR–TKI therapy. The patients were classified into two groups with low IL-8 expression and those with high IL-8 expression according to the median IL-8 level. Differences in DFS and OS were analysed with the log-rank test. Comparison of (C) DFS and (D) OS in four subgroups according to IL-8 expression levels and KRAS mutation status. KRAS-WT, KRAS wild-type; KRAS-Mut, KRAS-mutant. Differences in DFS and OS between IL-8-High/KRAS-Mut and IL-8-Low/KRAS-WT were analysed with the log-rank test with Bonferroni's correction for multiple comparisons.