The role of Phosphatidylinositol 3 kinase (PI3K) and Cycloxygenase-2 (COX2) in carcinogenesis of colorectal polyps / O papel de PI3K e COX2 na carcinogênese de pólipos colorretais

ABSTRACT Objectives: Determine immunohistochemical expression of Phosphatase and tensin homolog (PTEN), Phosphatidylinositol 3 kinase (PI3K), Cycloxygenase-2 (COX2) and one proliferation marker (Ki67) in colorectal polyps and correlate with clinical and pathological data in search of carcinogenic pathways. Methods: The reports of 297 polyps diagnosed through endoscopy were reviewed for parameters including age, gender, prior colorectal cancer, the presence of multiple polyps, and polyps' location, appearance and size. Was conducted a microscopic morphometric computerized analysis of immunohistochemical expression using, the selected antibodies and correlated with clinical and pathological variables. Results: The tissue immunohistochemical expression was higher in right colon polyps for the proliferation marker and Phosphatidylinositol 3 kinase (p ≤ 0.0001 and 0.057 respectively). Cycloxygenase-2 and Phosphatase and tensin homolog demonstrated higher tissue immunoexpression in pedunculated polyps (p = 0.009 and 0.002 respectively). Cycloxygenase-2 exhibited higher immunoexpression in larger polyps (p = 0.005). Phosphatidylinositol 3 kinase, Cycloxygenase-2, Phosphatase and tensin homolog and the proliferation marker exhibited higher immunoexpression in high-grade dysplastic polyps (p = 0.031, 0.013, 0.044 and <0.001 respectively). Phosphatase and tensin homolog labeling was higher in polyps with high-grade dysplasia and lower in some of serrated lesions (p = 0.044). Conclusions: The greater expression of the proliferation marker and Phosphatidylinositol 3 kinase in the right colon may be related to right-sided colorectal carcinogenesis. The proliferation marker, Cycloxygenase-2 and Phosphatidylinositol 3 kinase results can be associated with progression of polyps to colorectal cancer. The higher Phosphatase and tensin homolog expression suggests its attempt to control the cell cycle.

RESUMO Objetivos: Determinar a expressão imuno-histoquímica de Fosfatase homóloga a tensina (PTEN), Fosfatidilinositol-3-cinase (PI3K), Ciclooxigenase-2 (COX2) e um marcador de proliferação (Ki67) em pólipos colorretais e correlacionar com dados clínicos e patológicos buscando sua correspondência na carcinogênese. Métodos: Revisados 297 pólipos diagnosticados através de endoscopia quanto a idade, gênero, história de câncer colorretal, número, localização, aparência e tamanho dos pólipos. Realizadas as avaliações morfométricas computadorizadas das expressões imuno-histoquímicas dos marcadores selecionados, que foram correlacionadas com variáveis clínicas e patológicas. Resultados: A expressão do marcador de proliferação e da Fosfatidilinositol-3-cinase foi maior nos pólipos do cólon direito (p = <0,0001 e 0.057 respectivamente). Ciclooxigenase-2 e Fosfatase homóloga a tensina demonstraram maior imunoexpressão em pólipos pediculados (p = 0,009 e 0,002, respectivamente). Ciclooxigenase-2 expressou mais em pólipos maiores (p = 0,005). Fosfatidilinositol-3-cinase, Ciclooxigenase-2, Fosfatase homóloga a tensina e o marcador de proliferação expressaram mais em pólipos com displasia de alto grau (p = 0,031, 0,013, 0,044 e <0,001, respectivamente). Fosfatase homóloga a tensina marcou mais pólipos com displasia de alto grau que lesões serrilhadas (p = 0,044). Conclusões: A maior expressão do marcador de proliferação e Fosfatidilinositol-3-cinase à direita pode estar relacionada à carcinogênese do lado direito do cólon. Os resultados do marcador de proliferação, Ciclooxigenase-2 e Fosfatidilinositol-3-cinase podem ser associados à progressão dos pólipos para câncer. A expressão aumentada de Fosfatase homóloga a tensina sugere tentativa de controle do ciclo celular.

Leishmania donovani secretory serine protease alters macrophage inflammatory response via COX-2 mediated PGE-2 production.

Leishmania parasites determine the outcome of the infection by inducing inflammatory response that suppresses macrophage’s activation. Defense against Leishmania is dependent on Th1 inflammatory response by turning off macrophages’ microbicidal property by upregulation of COX-2, as well as immunosuppressive PGE-2 production. To understand the role of L. donovani secretory serine protease (pSP) in these phenomena, pSP was inhibited by its antibody and serine protease inhibitor, aprotinin. Western blot and TAME assay demonstrated that pSP antibody and aprotinin significantly inhibited protease activity in the live Leishmania cells and reduced infection index of L. donovani-infected macrophages. Additionally, ELISA and RT-PCR analysis showed that treatment with pSP antibody or aprotinin hold back COX-2-mediated immunosuppressive PGE-2 secretion with enhancement of Th1 cytokine like IL-12 expression. This was also supported in Griess test and NBT assay, where inhibition of pSP with its inhibitors elevated ROS and NO production. Overall, our study implies the pSP is involved in down-regulation of macrophage microbicidal activity by inducing host inflammatory responses in terms of COX-2-mediated PGE-2 release with diminished reactive oxygen species generation and thus suggests its importance as a novel drug target of visceral leishmaniasis.

Detection of cyclooxygenase-2 [COX-2] expression in non-small cell lung carcinoma. An immunohistochemical and computerized image analysis study

Lung cancer is the leading cause of cancer death all over the world. Evidence is accumulating to suggest that cyclooxygenase-2 [COX-2] is involved the pathogenesis and progression of some types of lung cancer. COX-2 is one of the novel targets under evaluation for non-small cell lung carcinoma [NSCLC] therapy and chemoprevention. The aim of the present study was to detect COX-2 expression in non-small cell lung carcinoma [NSCLC] and to determine its correlation with various clinic pathological parameters. The expression of COX-2 was assessed in 30 patients with NSCLC using immunohistochemistry, followed by quantitative assessment of the immunostaining using computerized image analysis. The present work was conducted on 30 patients with NSCLC: squamous cell carcinoma [15 patients], adenocarcinoma [10 patients], and undifferentiated large cell carcinoma [5 patients]. Overall, 70% of studied NSCLC expressed COX-2. 60% of squamous cell carcinoma [SCC], 80% of adenocarcinoma [ADC] and 80% of undifferentiated large cell carcinoma [ULCC] showed positive immunostaining for COX-2. No significant correlation was found between tumor histological type and each of frequency and degree of COX-2 expression [p=0.569 and p=0.094 respectively]. Though the expression of COX-2 increased with tumor grade, the relation between COX2 expression [both the frequency and degree of expression] and tumor grade was not significant [p=0.778 and p=0.247 respectively for SCC, and p=0.641 and p=0.067 respectively for ADC]. A statistically significant difference was found between node positive and node negative cases as regards the degree of COX2 expression [p=0.05]. No significant relationship was found between COX-2 expression and age and sex of patients, smoking and tumor stage. COX-2 is frequently overexpressed in NSCLC especially in adenocarcinoma and undifferentiated large cell carcinoma. Expression was higher in node-positive tumors and tended to increase with tumor grade, suggesting that COX-2 might play a role in the pathogenesis and/or progression of these tumors. COX-2 appears to be a potentially promising target for therapy and chemoprevention of NSCLC

The Change of Cyclooxygenase-2 and Inducible Nitric Oxide Synthase in the Gastric Mucosa One Year after Eradication of Helicobacter pylori / 대한소화기학회지

BACKGROUND/AIMS: The cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), the proteins that have the role in the gastric carcinogenesis, are stimulated by H. pylori infection in the gastric mucosa. The aim of this study was to evaluate the expression of COX-2 and iNOS proteins one year after the eradication of H. pylori. METHODS: Gastric antral mucosa from fifty eight patients with chronic gastritis who were all infected with H. pylori was examined for the expression of COX-2 and iNOS proteins before and one year after the eradication of H. pylori by immunohistochemical stain. RESULTS: COX-2 and iNOS proteins were expressed in the epithelial cells and interstitial inflammatory cells of gastric mucosa. Percent expressions of COX-2 and iNOS were significantly decreased one year after the eradication in the patients with cured infection, but not in those having persistent H. pylori. COX-2 and iNOS expressions were well correlated with H. pylori density, acute and chronic inflammation of gastric mucosa. CONCLUSIONS: The eradication of H. pylori can decrease the expression of COX-2 and iNOS in the gastric mucosa in long-term period. This seems to be due to the removal of H. pylori itself and related regression of gastric inflammation.