Interleukin-8/CXCL8 is a growth factor for human lung cancer cell

Department of Clinical Oncology, Institute for Cancer Studies, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
British Journal of Cancer (Impact Factor: 4.84). 11/2004; 91(11):1970-6. DOI: 10.1038/sj.bjc.6602227
Source: PubMed


Interleukin-8/CXCL8 (IL-8) is a chemokine and angiogenic factor. Recently, IL-8 was identified as an autocrine growth factor in several human cancers. Here, we investigated the expression and function of IL-8 in lung cancer cells. The expressions of IL-8 and its receptors, CXCR1 and CXCR2, were examined in a panel of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines. Using reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay, we found that all NSCLC cell lines tested produced modest or high levels of IL-8 (up to 51 ng ml(-1) 10(6) cells(-1)). Expression of CXCR1 and CXCR2 was found by RT-PCR and flow cytometry in two out of three cell lines. In contrast, SCLC cell lines produced very low or undetectable levels of IL-8, but expressed CXCR1 and CXCR2. We next investigated whether IL-8 could act as an autocrine growth factor in two NSCLC cell lines (H460 and MOR/P) expressing both IL-8 and its receptors. We found that cell proliferation was attenuated by anti-IL-8 neutralising antibody to 71 and 76% in H460 and MOR/P, respectively (P<0.05). Exogenous IL-8 significantly stimulated cell proliferation in four SCLC cell lines tested in a dose-dependent fashion. Cell proliferation was increased by between 18% (P<0.05) and 37% (P<0.05). Stimulation of cell proliferation by IL-8 was also demonstrated by analysis of proliferating cell nuclear antigen expression and cell cycle in H69 cells. Furthermore, we investigated which receptor(s) mediated the mitogenic function of IL-8 in lung cancer cells. We found that cell proliferation was significantly reduced by anti-CXCR1 antibody but not by anti-CXCR2 antibody. In conclusion, IL-8 can act as an autocrine and/or paracrine growth factor for lung cancer cells, and the mitogenic function of IL-8 in lung cancer is mediated mainly by CXCR1 receptor.

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    • "A 20 μL portion of the RT products was then brought to a volume of 20 μL containing 10 mM of each dNTP, 1 U of Taq polymerase (Promega, Madison, USA), 10 pmol of both the upstream and downstream PCR primers, and 1 x PCR buffer (proprietary formulation supplied at pH 8.5 containing blue dye and yellow dye) provided by Promega. The primers for IL-8 are as follows: forward, 5′-ATG ACT TCC AAG CTG GCC GTG GCT-3′ and reverse, 5′-TCT CAG CCC TCT TCA AAA ACT TCT-3′ with a product of 289 bps [34]. For glyceraldehyde-3-phosphate dehydrogenase (GAPDH); the forward primer was 5′-CCAGCCGAGCCACATCGCTC-3; and the reverse primer was 5′-ATGAGCCCCAGCCTTCTCCAT-3′, giving a 390 bps PCR product. "
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    ABSTRACT: Human parainfluenza virus type 1 (HPIV-1) is the most common cause of croup in infants. The aim of this study was to describe molecular mechanisms associated with IL-8 production during HPIV-1 infection and the role of viral replication in MAPK synthesis and activation. An in vitro model of HPIV-1 infection in the HEp-2 and A549 cell lines was used; a kinetic-based ELISA for IL-8 detection was also used, phosphorylation of the mitogen-activated protein kinases (MAPKs) was identified by Western blot analysis, and specific inhibitors for each kinase were used to identify which MAPK was involved. Inactivated viruses were used to assess whether viral replication is required for IL-8 production. Results revealed a gradual increase in IL-8 production at different selected times, when phosphorylation of MAPK was detected. The secretion of IL-8 in the two cell lines infected with the HPIV-1 is related to the phosphorylation of the MAPK as well as viral replication. Inhibition of p38 suppressed the secretion of IL-8 in the HEp-2 cells. No kinase activation was observed when viruses were inactivated.
    Research Journal of Immunology 06/2014; 2014(2):515984. DOI:10.1155/2014/515984
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    • "Subsequently, we reported that IL-8 expression is transcriptionally upregulated by oncogenic KRAS mutations in NSCLC (Sunaga et al, 2012). IL-8 is an essential proinflammatory mediator that is involved in cancer development and acts as an angiogenic growth factor that promotes cell proliferation and angiogenesis, thus contributing to the progression and metastasis of NSCLC (Smith et al, 1994; Arenberg et al, 1996; Wang et al, 1996; Yatsunami et al, 1997; Zhu et al, 2004; Boldrini et al, 2005; Luppi et al, 2007). IL-8 has also been implicated in the epithelial–mesenchymal transition and cancer cell stemness during tumour progression (Palena et al, 2012). "
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    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.
    British Journal of Cancer 02/2014; 110(8). DOI:10.1038/bjc.2014.110 · 4.84 Impact Factor
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    • "Since CXCL8 is not the only chemokine expressed under such circumstances, determination of its specific role is difficult. Various signals and/or pathways induce CXCL8 expression in cancers [40]. The activation of oncogenes may be linked to inflammatory signaling via the cell-intrinsic mechanism described above. "
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    ABSTRACT: Although the functions of chemokines in the regulation of immune processes have been studied in some detail, the role of these biomolecules in cancer is not fully understood. Chemokines mediate migration of immune cells and other functions related to immunity. They are also involved in oncogenesis and in tumor progression, invasion, and metastasis through mechanisms similar to their roles in immune functions. Various chemokines also promote cell proliferation and resistance to apoptosis of stressed cells. Consequently, chemokines and their receptors present potential therapeutic targets for anticancer drugs. The chemokine CXCL8, also known as interleukin-8 (IL8), is a proinflammatory molecule that has functions within the tumor microenvironment. Due to its potent angiogenic effects and the activity of the chemokine and its receptors in the promotion of invasion and metastasis, CXCL8 and its receptors are now considered as attractive targets for cancer therapy. This review relates the current understanding of the regulation, signaling, and functions of CXCL8 that contribute to tumor growth and metastasis, and of its role in drug response.
    10/2013; 2013(2):859154. DOI:10.1155/2013/859154
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