Kuzbicki L, Sarnecka A, Chwirot BWExpression of cyclooxygenase-2 in benign naevi and during human cutaneous melanoma progression. Melanoma Res 16:29-36
Department of Medical Biology, Institute of General and Molecular Biology, Nicolaus Copernicus University, Toruń, Poland. Melanoma Research
(Impact Factor: 2.28).
03/2006; 16(1):29-36. DOI: 10.1097/01.cmr.0000194430.77643.a0
Cyclooxygenase-2 (COX-2) is an enzyme that plays an important role in the production of prostaglandins. Numerous studies have demonstrated increased levels of COX-2 in human cancers of different types. It is thought that COX-2 may be involved in the development and progression of malignant tumours. However, data on the changes in COX-2 expression during the development and progression of human melanoma are relatively limited. Moreover, the results reported by different groups disagree to a large extent. The aim of this work was to evaluate whether COX-2 protein might be considered a potential molecular marker of melanoma progression. The expression of COX-2 was determined immunohistochemically in formalin-fixed, paraffin-embedded specimens of 64 human melanocytic skin tumours (17 naevi, 36 primary cutaneous melanomas and 11 lymph node melanoma metastases, with six pairs of primary and metastatic lesions obtained from the same patients). It was found that the expression level of COX-2 was dependent on both the stage and histopathological type of the melanoma. Collectively, our data indicate that changes in the expression level of COX-2 are correlated with the development and progression of human melanoma, and imply that the COX-2 protein may be considered a potential prognostic and predictive marker in malignant melanoma.
Available from: Jens Pietzsch
- "In a study of Becker et al. (2009), COX-2 was found in 95 % of melanoma revealing a significant correlation between immunohistochemical staining intensity and Breslow index. Kuzbicki et al. (2006) reported a coherency between COX-2 expression and development as well as progression of human melanoma. Thus, COX-2 was suggested to be a potential prognostic and predictive marker. "
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ABSTRACT: Melanoma is the most malignant type of all skin neoplasms. Its worldwide incidence has steadily increased during the past decades, suggesting a probable melanoma 'epidemic'. Although current clinical, morphologic, and histopathologic methods provide insights into disease behavior and outcome, melanoma is still an unpredictable disease. Once in an advanced stage, it remains a disastrous affliction with scarce therapeutic options. Therefore, significant efforts need to be made in finding informative biomarkers or surrogate markers that could aid or improve early diagnosis of melanoma, its correct staging, the discrimination of other pathological conditions as well as indicate patients' prognosis or the most appropriate therapeutic regimes. Ideally these markers are secreted into body fluids and easily amenable to the design of non-invasive clinical tests. A critical view on the current debate on serologic protein markers, e.g., lactate dehydrogenase, tyrosinase, and melanoma inhibiting activity, and some selected non-protein markers, e.g., 5-S-cysteinyl-dopa and circulating nucleic acids, will be offered and novel innovative approaches currently being explored will be discussed. Special emphasis is put on the S100 family of calcium binding proteins that is more and more emerging as a potentially important group of both molecular key players and biomarkers in the etiology, progression, manifestation, and therapy of neoplastic disorders, including malignant melanoma. Notably, S100B and, possibly, other S100 proteins like S100A4 are assumed to fulfill requirements which make them strong biomarker candidates in melanoma. Moreover, S100 proteins receive attention as possible targets of therapeutic intervention moving closer to clinical impact.
Available from: Jane Armstrong
- "In the context of melanoma, increased expression of the NFAT target gene cyclooxygenase-2 (COX-2), an inducible enzyme involved in the conversion of arachidonic acid to prostaglandins, correlates with poor prognosis (Kuzbicki et al, 2006; Chwirot and Kuzbicki, 2007), suggesting that NFAT signalling may be important in melanoma. However, upstream activators of COX-2 in melanoma and a role for oncogene-driven NFAT activation remain undefined. "
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ABSTRACT: Metastatic melanoma is the most deadly form of skin cancer and with an overall 5-year survival rate of <11%, there is an acute need for novel therapeutic strategies. Activating mutations in the BRAF oncogene are present in 50-70% of cases and contribute to tumourigenesis, thus, defining downstream targets of oncogenic BRAF may help define novel targets for therapeutic intervention. The Ca(2+)/calcineurin-regulated transcription factor, Nuclear factor of activated T-cells (NFAT), is important in the pathogenesis of several human cancers, target genes of which are also known to contribute to melanoma progression. One such NFAT target gene is COX-2, increased expression of which correlates with poor prognosis; however, upstream regulators of COX-2 in melanoma remain undefined. Therefore, the aim of this study was to evaluate NFAT expression and activity in metastatic melanoma and establish whether or not oncogenic BRAF signalling modulates NFAT activity and determine if NFAT is a key upstream regulator of COX-2 in melanoma.
Nuclear factor of activated T-cells transcriptional activity and protein expression were determined in three human metastatic melanoma cell lines with differing B-RAF mutational status. NFAT activation by oncogenic BRAF(V600E) was explored by BRAF(V600E) overexpression and application of the specific MEK inhibitor PD98059. Regulation of COX-2 expression by NFAT was investigated using NFAT-targeted siRNA, calcineurin inhibitors cyclosporin A and FK506, in addition to COX-2 luciferase reporter vectors that selectively lacked NFAT binding sites.
NFAT transcriptional activity was increased in BRAF-mutated melanoma cells compared with wild-type cells. Furthermore, in wild-type cells, overexpression of BRAF(V600E) increased NFAT activity, which was blocked by the MEK inhibitor PD98059. Using calcineurin inhibitors and siRNA-mediated knockdown of NFAT2 and 4, we show NFAT is required for COX-2 promoter activation and protein induction in metastatic melanoma cells.
NFAT2 and 4 are expressed in human metastatic melanoma cell lines and are activated by oncogenic BRAF(V600E) via MEK/ERK signalling. NFAT is an important upstream regulator of COX-2 in metastatic melanoma. Furthermore, as the BRAF/MEK/ERK pathway is hyperactive in other malignancies and MEK/ERK are also activated by oncogenic RAS in 30% of all human cancers, the potential to exploit NFAT signalling for therapeutic benefit warrants further investigation.
Available from: Tamar Nijsten
- "However, NSAIDs may inhibit cancer through various COXindependent pathways as well (Marx, 2001; Elwood et al., 2009). This could be of particular importance in CM, as NSAIDs inhibit the growth of CM cell lines independent of COX-2 (Vogt et al., 2001; Xu, 2002; Chiu et al., 2005; Bundscherer et al., 2008; Lee et al., 2008), and COX-2 is not consistently expressed in CM (Denkert et al., 2001; Vogt et al., 2001; Goulet et al., 2003; Nettelbeck et al., 2003; Kuzbicki et al., 2006; Lee et al., 2008). Thus far, most of the epidemiological studies assessing the chemoprophylactic effects of NSAIDs on CM incidence focus "
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ABSTRACT: This case-control study investigates the potential chemoprophylactic properties of non-steroidal anti-inflammatory drugs (NSAIDs) on the incidence of cutaneous melanoma (CM). Data were extracted from the Dutch PHARMO pharmacy database and the PALGA pathology database. Cases had a primary CM between 1991 and 2004, were >or=18 years, and were observed for 3 years in PHARMO before diagnosis. Controls were matched for date of birth, gender, and geographical region. NSAIDs and acetylsalicylic acids (ASAs) were analyzed separately. Adjusted odds ratio (OR) and 95% confidence interval (CI) were calculated using multivariable logistic regression, and the results were stratified across gender. A total of 1,318 CM cases and 6,786 controls were eligible to enter the study. CM incidence was not significantly associated with ever ASA use (adjusted OR: 0.92, 95% CI: 0.76-1.12) or ever non-ASA NSAID use (adjusted OR: 1.10, 95% CI: 0.97-1.24). However, continuous use of low-dose ASAs was associated with a significant reduction of CM risk in women (adjusted OR: 0.54, 95% CI: 0.30-0.99) but not in men (OR: 1.01, 95% CI: 0.69-1.47). A significant trend (P=0.04) from no use, non-continuous use to continuous use was observed in women. Continuous use of low-dose ASAs may be associated with a reduced incidence of CM in women, but not in men.
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