3579

CXCR2

chemokine (C-X-C motif) receptor 2;CXCR2;chemokine (C-X-C motif) receptor 2

C-X-C chemokine receptor type 2|CXC-R2|CXCR-2|CXCR2 gene for IL8 receptor type B|GRO/MGSA receptor|IL-8 receptor type 2|IL-8R B|chemokine (CXC) receptor 2|high affinity interleukin-8 receptor B|interleukin 8 receptor B|interleukin 8 receptor type 2|interl

2q35

protein-coding

AIMS: The liver and lung are the organs most commonly affected by metastasis in colorectal cancer (CRC), and the interaction of chemokines and chemokine receptors (CKRs) plays an important role in the metastatic process. The aim of this study was to investigate the organ specificity of CKRs in CRC distant metastasis. METHODS AND RESULTS: Surgical specimens of primary tumours from 46 patients with metachronous distant metastases were retrieved retrospectively (20 lung metastases; 26 liver metastases). As a control, the records of 29 patients without distant metastases were randomly retrieved from our database, and their specimens were reassessed. The expression rates of CKRs, including CCR6, CXCR2, and CXCR4, were determined by immunohistochemistry, and were compared among the groups. The expression rates of CCR6 and CXCR2 were both significantly higher in the metastasis group than in the non-metastasis group (P < 0.05), but there was no statistical difference between the lung metastasis and liver metastasis subgroups. The expression of CXCR4 was not significantly different between the metastasis and non-metastasis groups. Multivariable analysis suggested that preoperative serum carcinoembryonic antigen level, CCR6 and CXCR2 were independent factors associated with distant metastasis. CONCLUSIONS: The expression of CCR6 and CXCR2 in CRC could predict metachronous distant metastasis, but they have no organ specificity for metastasis.

CXC chemokines have been reported to play critical roles in tumor growth, angiogenesis, invasion and metastasis of various human cancers. However, expression of CXC chemokines type 2 (CXCR2) and its association with clinicopathological characters and patients' prognosis in esophageal cancer are scarcely reported. We retrospectively collected clinicopathologic characteristics of 95 esophageal cancer patients undergoing esophagectomies. Immunohistochemistry was used to detect the expression of CXCR2. The survival was analyzed by the Kaplan-Meier method. Univariate and multivariate analyses were then performed to determine the relationship between CXCR2 and the clinical characteristics and to analyze whether CXCR2 expression was a significant independent prognostic factor for esophageal cancer patients. CXCR2 was highly expressed in 57.9 % of the randomly selected specimens. The expression of CXCR2 was significantly related to lymph node metastasis (P = 0.044) and predicted poor overall status in operable esophageal cancer patients (P = 0.012). Cox proportional hazard analysis regression analysis indicated that CXCR2 expression (P = 0.030) and lymphatic metastasis (P < 0.001) may serve as independent prognostic markers for esophageal cancer patients. Our results demonstrate that CXCR2 significantly correlates with lymph node metastasis and is a poor prognostic factor in resected esophageal squamous cell carcinoma.

BACKGROUND: An ELR+ CXC chemokine receptor, CXCR2, was recently reported to be involved in tumorigenesis and development. However, the role of CXCR2 in hepatocellular carcinoma (HCC) is poorly understood. In this study, we aimed to investigate the association between CXCR2 expression and the biocharacteristics of HCC, and determine whether the expression of CXCR2 was related to the tumorigenesis and progression. METHODS: Forty-two patients who underwent hepatic resection and were diagnosed as HCC by histologic examination were included. HCC and corresponding adjacent tissues (distance from the tumor border exceeding 2 cm) were obtained. Twenty-three samples of normal liver tissue were acquired surgically from the patients who had received an operation due to liver trauma. CXCR2 mRNA and protein expressions were examined using semiquantitative reverse transcription-PCR and Western blot. RESULTS: expression levels of CXCR2 were significantly increased in HCC compared with adjacent and normal liver tissues (P < 0.05). The results showed that CXCR2 mRNA and protein expression levels were not related to age, gender, AFP levels, tumor capsule, or tumor size. Also, there was no relationship between CXCR2 mRNA expression and TNM staging. The expression levels of CXCR2 mRNA and protein were correlated with intrahepatic metastasis (P < 0.05), portal cancer embolus (P < 0.05), and low differentiation (P < 0.05). Furthermore, the protein level of CXCR2 was relevant to TNM staging. The protein level of CXCR2 in stage III-IV was remarkably higher than in stage I-II (P < 0.05). CONCLUSION: Our data revealed that CXCR2 was able to promote invasion and metastasis of HCC. It may be a useful marker for judging biocharacteristics and prognosis of HCC.

In the present study, we examined the autocrine/paracrine role of IL-8 in melanoma growth and metastasis by analyzing the expression and functional significance of IL-8 receptors, CXCR1 and CXCR2 in human malignant melanoma cells with different metastatic potential. CXCR1 and CXCR2 mRNA and protein levels were analyzed by reverse trannscriptase-based polymerase chain reaction, immunohistochemistry, immunoprecipitation, flow cytometry and ligand binding assay in melanoma cells in vitro and xenografted in nude mice. Melanoma cells constitutively expressed CXCR1 and CXCR2 mRNA and protein. Highly metastatic A375SM cells expressed higher levels of CXCR1 and CXCR2 mRNA and protein in vitro and in vivo as compared to low metastatic A375P and non-metastatic SBC-2 melanoma cells. Treatment of SBC-2 and A375P cells with exogenously added recombinant IL-8 significantly enhanced their proliferation and invasive potential. Further neutralizing antibodies to CXCR1 and CXCR2 inhibited proliferation and invasive potential of unstimulated and IL-8-stimulated A375P cells. In summary, the data suggest that constitutive expression of CXCR1 and CXCR2 play an important role regulating the IL-8-mediated metastatic phenotype in human malignant melanoma cells.

Crucial steps in tumor growth and metastasis are proliferation, survival, and neovascularization. Previously, we have shown that receptors for CXCL-8, CXCR1, and CXCR2 are expressed on endothelial cells and CXCR2 has been shown to be a putative receptor for angiogenic chemokines. In this report, we examined whether tumor angiogenesis and growth of CXCL-8-expressing human melanoma cells are regulated in vivo by a host CXCR2-dependent mechanism. We generated mCXCR2(-/-), mCXCR2(+/-), and wild-type nude mice following crosses between BALB/c mice heterozygous for nude(+/-) and heterozygous for mCXCR2(+/-). We observed a significant inhibition of human melanoma tumor growth and experimental lung metastasis in mCXCR2(-/-) mice as compared with wild-type nude mice. Inhibition in tumor growth and metastasis was associated with a decrease in melanoma cell proliferation, survival, inflammatory response, and angiogenesis. Together, these studies show the importance of host CXCR2-dependent CXCL-8-mediated angiogenesis in the regulation of melanoma growth and metastasis.

BACKGROUND: Chemokine receptor signaling pathways are implicated in the pathobiology of renal cell carcinoma (RCC). However, the clinical relevance of CXCR2 receptor, mediating the effects of all angiogenic chemokines, remains unclear. SOCS (suppressor of cytokine signaling)-3 is a negative regulator of cytokine-driven responses, contributing to interferon-alpha resistance commonly used to treat advanced RCC with limited information regarding its expression in RCC. METHODS: In this study, CXCR2 and SOCS-3 were immunohistochemically investigated in 118 RCC cases in relation to interleukin (IL)-6 and (IL)-8, their downstream transducer phosphorylated (p-)STAT-3, and VEGF expression, being further correlated with microvascular characteristics, clinicopathological features and survival. In 30 cases relationships with hypoxia-inducible factors, i.e. HIF-1a, p53 and NF-kappaBeta (p65/RelA) were also examined. Validation of immunohistochemistry and further investigation of downstream transducers, p-JAK2 and p-c-Jun were evaluated by Western immunoblotting in 5 cases. RESULTS: Both CXCR2 and IL-8 were expressed by the neoplastic cells their levels being interrelated. CXCR2 strongly correlated with the levels of HIF-1a, p53 and p65/RelA in the neoplastic cells. Although SOCS-3 was simultaneously expressed with p-STAT-3, its levels tended to show an inverse relationship with p-JAK-2 and p-c-Jun in Western blots and were positively correlated with HIF-1a, p53 and p65/p65/RelA expression. Neither CXCR2 nor SOCS-3 correlated with the extent of microvascular network. IL-8 and CXCR2 expression was associated with high grade, advanced stage and the presence/number of metastases but only CXCR2 adversely affected survival in univariate analysis. Elevated SOCS-3 expression was associated with progression, the presence/number of metastasis and shortened survival in both univariate and multivariate analysis. CONCLUSIONS: Our findings implicate SOCS-3 overexpression in RCC metastasis and biologic aggressiveness advocating its therapeutic targeting. IL-8/CXCR2 signaling also contributes to the metastatic phenotype of RCC cells but appears of lesser prognostic utility. Both CXCR2 and SOCS-3 appear to be related to transcription factors induced under hypoxia.