Loss of β-arrestin-2 and Activation of CXCR2 Correlate with Lymph Node Metastasis in Non-small Cell Lung Cancer

Abstract

Background : Although β-arrestin-2 (β-arr2) and CXCR2 have been shown to affect various malignant tumors, their exact roles in lung cancer remain unclear. We investigated expression of β-arr2 and CXCR2 in patients with non-small cell lung cancer (NSCLC) and their correlation with lymph node metastasis and prognosis. Methods : We reviewed medical records of 136 patients with NSCLC who underwent surgical resection, and assessed their specimens immunohistochemically for expression of β-arr2 and CXCR2 in primary tumors and metastatic lymph nodes (MLNs), respectively. Results: High β-arr2 expression was seen in 63 specimens (46.3%), and was significantly associated with male patients (P=0.011), squamous cell carcinoma (P=0.003), and lymph node metastasis (P<0.001). High CXCR2 expression was seen in 62 specimens (45.6%), and was significantly correlated only with lymph node metastasis (P<0.001). Expression of β-arr2 was significantly lower at MLNs than at primary lesions (Z=-2.315; P=0.021; Wilcoxon signed-rank), whereas CXCR2 expression was significantly higher in MLNs than in primary lesions (Z=-3.712; P<0.001; Wilcoxon signed-rank). No relationship was seen between β-arr2 and CXCR2 expression in primary lesions (r=-0.065, P=0.548; Spearman rank coefficient), but they were inversely related in MLNs (r=-0.263, P=0.012). Kaplan-Meier survival curve was shown that low β-arr2 and high CXCR2 expressions was associated with poor survival (log-rank: χ²=5.926, P=0.015). Conclusions : β-arr2 may promote lymph node metastasis in NSCLC by modulating CXCR2 activation.

Keywords: CXCR2; immunohistochemistry.; non-small cell lung cancer; β-arrestin-2.

Figure 1

Expressions of β-arrestin-2 (β-arr2) and CXCR2 in adenocarcinoma (ADC) and squamous cell carcinoma (SCC). A. Western blot showed β-arr2 (mw: 50 kDa) and CXCR2 (mw: 41 kDa) expression in NSCLC cell lines and 8 surgical specimens (4 SCC and 4 ADC). B. Immunohistochemical staining is shown for β-arr2 in NSCLC (scale bar: 50 µm). C. Immunohistochemical staining is shown for CXCR2 in NSCLC (scale bar: 50 µm).

Figure 2

Expression of β-arr2 and CXCR2 differ in primary NSCLC tumors and metastatic lymph nodes (MLN). A. Different expression of β-arr2 in primary tumors and MLN. B. Different expression of CXCR2 in primary tumors and MLN.

Figure 3

Analysis of β-arr2 and CXCR2 expressions in primary NSCLC tumors and MLNs (Spearman rank coefficient). No relationship was seen for primary tumors, however, an inverse relationship was seen in MLNs (r=-0.263, P=0.012).

Figure 4

Kaplan-Meier survival curve comparing NSCLC patients with β-arr2^High/CXCR2^Low expression (n=36) and those with β-arr2^Low/CXCR2^High expression (n=38) in metastatic lymph nodes. The β-arr2^Low/CXCR2^High group had significantly worse 4-year overall survival (Log-rank: χ²=5.926, P=0.015).