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.

C-X-C chemokine receptor 2 correlates with unfavorable prognosis and facilitates malignant cell activities via activating JAK2/STAT3 pathway in non-small cell lung cancer

“…Also, high expression of CXCR2 was associated with Dukes stage, tumor invasion and liver metastasis in colorectal cancer patients [21]. As for NSCLC, CXCR2 is highly expressed in primary tumors and metastatic lymph nodes of NSCLC, and the activation of CXCR2 promotes lymph node metastasis in NSCLC patients [17]. In accordance with the previous evidences, we observed that CXCR2 expression was higher in tumor tissues compared with paired adjacent tissues of SCLC.…”

“…As for NSCLC, the implication of CXCR2 is rarely reported, and only one study exhibits that CXCR2 is correlated with lymph node metastasis in NSCLC patients [17]. Besides, our preliminary study discovered that CXCR2 was overexpressed in both tumor tissues and cell lines of NSCLC, which promotes NSCLC cell proliferation.…”

New Routes in GPCR/β-Arrestin-Driven Signaling in Cancer Progression and Metastasis

“…Although β-arr1 and β-arr2 show high degree of sequence and structural similarity and functional overlap (Srivastava et al., 2015), emerging evidences establish an involvement of β-arr2 in cancer growth and progression, with contradictory results. Previous studies demonstrated that β-arr2 depletion promoted tumor growth and angiogenesis in a murine model of lung cancer (Raghuwanshi et al., 2008) and that low expression of β-arr2 is significantly associated with aggressive pathologic features and is predictive of poor patient prognosis, as observed in lung and hepatocellular carcinoma (Sun et al., 2016; Cong et al., 2017). In prostate cancer, β-arr2 inhibits cell viability and proliferation by downregulation of FOXO1 and represses AR signaling, and AR expression/activity negatively correlates with β-arr2 expression (Lakshmikanthan et al., 2009; Duan et al., 2015).…”

Screening and identification of key biomarkers in bladder carcinoma: Evidence from bioinformatics analysis

“…CXCR2, the co-receptor of IL-8 and CXCL1, is an important therapeutic target in a number of solid tumor types, including lung, breast, prostate, ovarian, colorectal and liver cancer ( 50 – 55 ). Xu et al ( 56 ) revealed that CXCR2 may promote breast cancer metastasis and chemoresistance via the suppression of AKT serine/threonine kinase 1 and activation of cyclooxygenase 2.…”