Expression of interleukin-1 receptor-associated kinase-1 in non-small cell lung carcinoma and preneoplastic lesions

Abstract

Purpose: To identify the pattern of interleukin-1 receptor-associated kinase (IRAK-1) protein expression in non-small cell lung carcinoma (NSCLC) and corresponding preneoplastic lesions.

Experimental design: Archived tissue from NSCLC (adenocarcinoma and squamous cell carcinoma; n = 306) and adjacent bronchial epithelial specimens (n = 315) were analyzed for the immunohistochemical expression of IRAK-1, and the findings were correlated with patients' clinicopathologic features. Furthermore, we investigated the correlation between IRAK-1 expression and expression of NF-kappaB and IL-1alpha in tumor specimens.

Results: NSCLC tumors showed significantly higher cytoplasmic and lower nuclear IRAK-1 expression than normal epithelium. Squamous dysplasias had significantly higher cytoplasmic IRAK-1 expression than normal epithelium. In tumors, a significant positive correlation was detected between IRAK-1 expression (nuclear and cytoplasmic; P = 0.011) and IL-1alpha cytoplasmic expression (P < 0.0001). The correlation between the expression of the markers and patients' clinicopathologic features varied according to tumor histologic type and sex. High IRAK-1 cytoplasmic expression correlated with worse recurrence-free survival in women with NSCLC [hazard ratio (HR), 2.204; P = 0.033], but not in men. In adenocarcinoma, combined low level of expression of nuclear IRAK-1 and NF-kappaB correlated significantly with worse overall (HR, 2.485; P = 0.007) and recurrence-free (HR, 3.058; P = 0.006) survivals in stage I/II patients.

Conclusions: IRAK-1 is frequently expressed in NSCLC tissue specimens, and this expression is an early phenomenon in the sequential development of lung cancer. IRAK-1 is a novel inflammation-related marker and a potential target for lung cancer chemopreventive strategies.

Fig. 1

A, Western blot analysis of IRAK-1 expression in the in vitro cell line model, which includes normal human bronchial epithelium (NHBE), premalignant (BEAS-2B, 1799, and 1198) and malignant (1170-I) cells, and in six NSCLC cell lines (H1792, SK-MES-1, A427, H1299, H596, and H460). B, IRAK-1 immunostaining using formalin-fixed and paraffin-embedded cell line pellets of the in vitro cell line model and the 1792 cell line. Original magnification, ×400.

Fig. 2

Immunohistochemical expression of IRAK-1 in the sequential pathogenesis of squamous cell carcinoma (Panel A) and adenocarcinoma (Panel B) sequences. Photomicrographs showing cytoplasmic and nuclear IRAK-1 immunostaining in normal and mildlyabnormal epithelia and NSCLC tumors. Original magnification, ×200

Fig. 3

IRAK-1 cytoplasmic expression scores by epithelial and tumor specimen histology. In the box-plots, white bar in tumors and black bar in epithelial samples indicate median scores, and x indicates mean scores.

Fig. 4

A, Kaplan-Meier curves showing IRAK-1 cytoplasmic expression and recurrence-free survival (RFS) in patients with NSCLC by sex. IRAK-1 cytoplasmic expression score: high > 200, and low ≤ 200. B, Kaplan-Meier curves illustrating the effect of combined nuclear IRAK-1 and NF-κB expression levels on overall survival (OS) and RFS in patients with NSCLC. IRAK-1 nuclear expression score: low ≤ 35; and NF-κB expression score: low < 20.75.