Cyclooxygenase-2-dependent expression of angiogenic CXC chemokines CXCL5/CXC ligand (CXCL) 5 and interleukin-8/CXCL8 in Human Non-Small cell lung cancer

Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
Cancer Research (Impact Factor: 9.33). 04/2004; 64(5):1853-60. DOI: 10.1158/0008-5472.CAN-03-3262
Source: PubMed


Elevated tumor cyclooxygenase (COX)-2 activity plays a multifaceted role in non-small cell lung cancer (NSCLC). To elucidate the role of COX-2 in the in vitro and in vivo expression of two known NSCLC angiogenic peptides, CXC ligand (CXCL) 8 and CXCL5, we studied two COX-2 gene-modified NSCLC cell lines, A549 and H157. COX-2 overexpression enhanced the in vitro expression of both CXCL8 and CXCL5. In contrast, specific COX-2 inhibition decreased the production of both peptides as well as nuclear translocation of nuclear factor kappaB. In a severe combined immunodeficient mouse model of human NSCLC, the enhanced tumor growth of COX-2-overexpressing tumors was inhibited by neutralizing anti-CXCL5 and anti-CXCL8 antisera. We conclude that COX-2 contributes to the progression of NSCLC tumorigenesis by enhancing the expression of angiogenic chemokines CXCL8 and CXCL5.

27 Reads
  • Source
    • "Increased expression of Cox-2 has been found in a variety of human malignancies, including HNSCC [14-16]. Previous studies have reported several mechanisms by which Cox-2 contributes to carcinogenesis as well as cancer progression, including the activation of carcinogens [17], resistance to apoptosis [18,19], immunosuppression [20,21], the promotion of angiogenesis [11,22], the stimulation of proliferation [23] and invasiveness [24], and the autocrine activity of estrogen [25]. Such a multifaceted function of Cox-2 in conferring the malignant phenotype strongly suggested that Cox-2 is an attractive preventive and therapeutic target for various cancers [12,13,26-29]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: The epithelial-to-mesenchymal transition (EMT) accompanied by the downregulation of E-cadherin has been thought to promote metastasis. Cyclooxygenase-2 (Cox-2) is presumed to contribute to cancer progression through its multifaceted function, and recently its inverse relationship with E-cadherin was suggested. The aim of the present study was to investigate whether selective Cox-2 inhibitors restore the expression of E-cadherin in head and neck squamous cell carcinoma (HNSCC) cells, and to examine the possible correlations of the expression levels of EMT-related molecules with clinicopathological factors in HNSCC. METHODS: We used quantitative real-time PCR to examine the effects of three selective Cox-2 inhibitors, i.e., celecoxib, NS-398, and SC-791 on the gene expressions of E-cadherin (CDH-1) and its transcriptional repressors (SIP1, Snail, Twist) in the human HNSCC cell lines HSC-2 and HSC-4. To evaluate the changes in E-cadherin expression on the cell surface, we used a flowcytometer and immunofluorescent staining in addition to Western blotting. We evaluated and statistically analyzed the clinicopathological factors and mRNA expressions of Cox-2, CDH-1 and its repressors in surgical specimens of 40 patients with tongue squamous cell carcinoma (TSCC). RESULTS: The selective Cox-2 inhibitors upregulated the E-cadherin expression on the cell surface of the HNSCC cells through the downregulation of its transcriptional repressors. The extent of this effect depended on the baseline expression levels of both E-cadherin and Cox-2 in each cell line. A univariate analysis showed that higher Cox-2 mRNA expression (p = 0.037), lower CDH-1 mRNA expression (p = 0.020), and advanced T-classification (p = 0.036) were significantly correlated with lymph node metastasis in TSCC. A multivariate logistic regression revealed that lower CDH-1 mRNA expression was the independent risk factor affecting lymph node metastasis (p = 0.041). CONCLUSIONS: These findings suggest that the appropriately selective administration of certain Cox-2 inhibitors may have an anti-metastatic effect through suppression of the EMT by restoring E-cadherin expression. In addition, the downregulation of CDH-1 resulting from the EMT may be closely involved in lymph node metastasis in TSCC.
    Journal of Experimental & Clinical Cancer Research 05/2014; 33(1):40. DOI:10.1186/1756-9966-33-40 · 4.43 Impact Factor
  • Source
    • "tumor cells can secrete CXCL-1,-2, and -5 to attract neutrophils and activate MMP-2 and -9 to degrade the extracellular matrix (ECM), leading to tumor metastasis (Kulbe et al., 2004; Põld et al., 2004). Silencing of ITGB8 resulted in decreased expression of CXCL-1, -2, -5 and reduced metastatic potential of the cancer cell lines A549 and PC9. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lung cancer is the leading cause of cancer death in the world and metastasis is an essential aspect of lung cancer progression. ITGB8 has been implicated in metastasis of human tumors. However, the molecular mechanism by which ITGB8 is involved in tumor metastasis is still unclear. In this study, we compared the gene expression profiles of human lung cancer cell lines A549 and PC9 by ITGB8 gene silencing with that of parent cells and negative control cells to comprehensively investigate ITGB8-mediated changes with respect to the metastatic potential and gene expression of human lung cancer cell lines. Our results showed that ITGB8 silencing cells exhibited significant cell cycle arrest and less adhesion and invasion abilities. We confirmed by Western blot, ELISA, and real-time PCR that the expression of metastasis-related genes CXCL1, CXCL2, CXCL5, MMP-2, and MMP-9 were significantly decreased while that of E-Cadherin and cystatin B were dramatically increased in A549- and PC9-ITGB8 silencing cells. Furthermore, silencing of ITGB8 caused Snail and NF-κB transcriptional activation, and MEK and Akt phosphorylation level changes in lung cancer cell lines. Our results indicated that ITGB8 may play an important role in metastasis of human lung cancer cells. The ITGB8 silencing may change the lung cancer cells to a less invasive phenotype through alteration in the expression of metastasis-related genes.
    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 09/2012; 295(9):1446-54. DOI:10.1002/ar.22521 · 1.54 Impact Factor
  • Source
    • "In vitro and in vivo expressions of both CXCL8 and CXCL5 are regulated by COX-2 in NSCLC. Another report demonstrated that COX-2 up-regulates the expression of these chemokines by activating NF-jB nuclear translocation, which led to enhanced NSCLC tumor growth and angiogenesis in vivo (Pold et al. 2004; Williams et al. 1999). Multiple signaling pathways including MAPK and NF-jB can lead to regulation of CXCR2. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rel/NF-κB transcription factors play a key role in modulating the response of immunoregulatory genes including cytokines and chemokines, cell adhesion molecules, acute phase proteins, and anti-microbial peptides. Furthermore, an array of genes important for angiogenesis, tumor invasion and metastasis is also regulated by nuclear factor-κB (NF-κB). Close association of NF-κB with inflammation and tumorigenesis makes it an attractive target for basic research as well as for pharmaceutical industries. Studies involving various animal and cellular models have revealed the importance of NF-κB in pathobiology of lung diseases. This review (a) describes structures, activities, and regulation of NF-κB family members; (b) provides information which implicates NF-κB in pathogenesis of pulmonary inflammation and cancer; and (c) discusses information about available synthetic and natural compounds which target NF-κB or specific components of NF-κB signal transduction pathway and which may provide the foundation for development of effective therapy for lung inflammation and bronchogenic carcinomas.
    Archivum Immunologiae et Therapiae Experimentalis 07/2011; 59(5):335-51. DOI:10.1007/s00005-011-0136-z · 3.18 Impact Factor
Show more