Cyclooxygenase-2 expression in hepatocellular carcinoma

BACKGROUND/AIMS: Cyclooxygenase-2 (Cox-2) is an isoform of cyclooxygenase, which is the key enzyme converting arachidonic acids to prostaglandins. It has been reported that Cox-2 is overexpressed in colon cancer, and that inhibition of this enzyme activity reduces colon cancer development in humans and animals. However, the significance of Cox-2 in human liver cancer is still unclear. To clarify significance of Cox-2 in liver cancer, we immunohistochemically examined expression of this enzyme in cancerous and non-cancerous tissues of hepatocellular carcinoma (HCC). METHODOLOGY: Twenty-nine patients with HCC were examined; 10 patients had well differentiated HCC, 10 had moderately differentiated HCC, and 9 had poorly differentiated HCC. RESULTS: Twenty-eight of 29 (97%) patients with HCC exhibited a positive staining. More intense staining of Cox-2 in cancer tissue rather than non-cancerous tissue was observed in 7 of 10 (70%) patients with well differentiated HCC, in 3 of 10 (30%) with moderately differentiated HCC, and in 3 of 9 (33%) with poorly differentiated HCC, respectively. Rate of higher expression of Cox-2 in cancer tissue rather than in non-cancerous tissue of well differentiated HCC was increased, compared to that of moderately and poorly differentiated HCC (7/10 vs. 6/19, p < 0.05). CONCLUSIONS: The results of the present study showed that Cox-2 is related to HCC whose histology is well differentiated.     

Cyclooxygenase-2 expression in thyroid nodules.

Factors contributing to the development of thyroid neoplasia remain poorly understood. Recent evidence indicates that overexpression of the inducible cyclooxygenase, COX-2, is important in the pathogenesis of epithelial carcinomas. These studies were undertaken to evaluate whether COX-2 is up-regulated in human thyroid neoplasia. Benign (n = 14), and malignant (n = 14) thyroid nodules were analyzed for expression of COX-2 mRNA by quantitative RT-PCR. Immunoblotting and immunohistochemistry were performed on representative samples. Three human thyroid cancer cell lines were similarly analyzed for COX-2 expression. Levels of COX-2 mRNA were significantly increased in thyroid nodule samples compared with adjacent thyroid tissue in the malignant specimens but not in the benign specimens. Additionally, COX-2 mRNA levels were significantly increased in malignant nodule samples compared with benign nodule samples. COX-2 protein expression was higher in 8 of 10 thyroid nodules compared with the adjacent tissue. Immunohistochemical analysis localized expression of COX-2 to the malignant epithelial cells. Immunofluorescence demonstrated COX-2 protein expression in all three thyroid cell lines. Finally, COX-2 expression could be detected by RT-PCR in fine needle aspiration specimens of thyroid nodules. These data indicate that COX-2 is up-regulated in human thyroid cancer, but not in benign thyroid nodules, and suggest that COX-2 expression may serve as a marker of malignancy in thyroid nodules.     

Cyclooxygenase-2 expression and inhibition in atherothrombosis

Arachidonic acid metabolism plays an important role in acute ischemic syndromes affecting the coronary or cerebrovascular territory, as reflected by biochemical measurements of eicosanoid biosynthesis and the results of inhibitor trials in these settings. Two cyclooxygenase (COX)-isozymes have been characterized, COX-1 and COX-2, that differ in terms of regulatory mechanisms of expression, tissue distribution, substrate specificity, preferential coupling to upstream and downstream enzymes, and susceptibility to inhibition by the extremely heterogeneous class of COX-inhibitors. Although the role of platelet COX-1 in acute coronary syndromes and ischemic stroke is firmly established through approximately 20 years of thromboxane metabolite measurements and aspirin trials, the role of COX-2 expression and inhibition in atherothrombosis is substantially uncertain, because the enzyme was first characterized in 1991 and selective COX-2 inhibitors became commercially available only in 1998. In this review, we discuss the pattern of expression of COX-2 in the cellular players of atherothrombosis, its role as a determinant of plaque "vulnerability," and the clinical consequences of COX-2 inhibition. Recent studies from our group suggest that variable expression of upstream and downstream enzymes in the prostanoid biosynthetic cascade may represent important determinants of the functional consequences of COX-2 expression and inhibition in different clinical settings.     

Cyclooxygenase-2 expression in gastroenteropancreatic neuroendocrine tumors

BACKGROUND/AIMS: The aim of this multicenter study was to investigate cyclooxygenase-2 protein expression in gastroenteropancreatic neuroendocrine tumors and to examine the relationship to various clinicopathological parameters. METHODOLOGY: Thirty-seven gastroenteropancreatic neuroendocrine tumor specimens were analyzed immunohistochemically. Correlations between expression and some parameters such as age, sex, tumor size, location, presence of multiple neuroendocrine tumor, lymphatic/vascular/muscularis propria invasion and lymph node metastases were evaluated. Results were interpreted as significant if p < 0.05. RESULTS: Mean age of patients (15 men/22 women) was 52 +/- 17. Tumor size varied between 0.1 and 12 cm. (mean; 3.17 +/- 3.29 cm). Expression was detected in 75% of cases and in 92% of gastric neuroendocrine tumors. Expression in mixed endocrine and non-endocrine carcinomas was found to be significantly higher than in well-differentiated neuroendocrine tumors and carcinomas (p = 0.016). A relationship was observed between overexpression and lymphatic and vascular invasion (p = 0.029). However, no significant correlation was found between expression and sex, tumor location, size, muscularis propria invasion and lymph node metastasis. CONCLUSIONS: Cyclooxygenase-2 expression may play a role in the evolution of gastroenteropancreatic neuroendocrine tumors. However, further studies are necessary to determine the importance of this role, prognostic relevance and whether cyclooxygenase isoenzyme can be a target for treatment in these tumors.     

环氧合酶-2与胰腺疾病

环氧合酶-2(COX-2)是炎症过程中一个诱导酶,在某些炎症疾病中发挥重要作用。此外,近年来各方面的研究还发现COX-2与某些人类肿瘤的发生和(或)发展有关。COX-2在肿瘤及炎症中的作用以及潜在的治疗意义成为近年来研究的热点。那么COX-2与胰腺疾病的关系又如何呢?本文就近年来COX-2与胰腺癌及胰腺炎的研究进展加以综述。     

第306例--头晕、乏力伴低热、黑便

病历摘要 患者女,17岁.因头昏乏力伴低热2周,反复柏油样黑便3 d,于2003年4月6日入院.入院前2周开始出现头昏乏力伴低热,3 d前出现恶心呕吐伴柏油便就诊当地医院,胃镜示浅表性胃炎.     

Cyclooxygenase-2 inhibition: Vascular inflammation and cardiovascular risk

The inducible isoform of cyclooxygenase-2 (COX-2) plays a role in pathophysiologic processes like inflammation and pain but is also constitutively expressed in tissues such as the kidney or vascular endothelium, where it exerts important physiologic functions. Although much evidence exists that implicates COX-2 in atherosclerosis, its role in this setting remains substantially uncertain. This observation is also confirmed by the results of clinical trials of selective COX-2 inhibitors. Treatment with these drugs, developed with the assumption that they would be as effective as nonselective COX inhibitors but without their gastrointestinal side effects, has been reported to be associated with an increased cardiovascular risk. In this article, we review the pattern of expression of COX-2 in the cellular players of atherothrombosis, its role as a determinant of plaque vulnerability, and the vascular effects on prostanoid inhibition by COX-2 inhibitors.     

Cyclooxygenase-2 expression in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence

OBJECTIVE: Increased expression of the inducible cyclooxygenase 2 (COX-2) enzyme has been detected in esophageal and colonic adenocarcinoma, and intake of aspirin and non-steroidal anti-inflammatory drugs, known COX-2 inhibitors, have been associated with reduced tumor formation. Elevated COX-2 mRNA but variable protein expression has been demonstrated in Barrett's epithelium, and we have, therefore, sought to evaluate the expression of COX-2 protein throughout the Barrett's metaplasia-dysplasia-adenocarcinoma sequence. METHODS: Paraffin-embedded esophageal biopsies from 56 different patients with Barrett's esophagus were analyzed for COX-2 expression by immunohistochemistry. Twenty contained nondysplastic intestinal and gastric metaplasia, 12 demonstrated low-grade dysplasia (LGD), 12 high-grade dysplasia (HGD), and 12 contained invasive adenocarcinoma. RESULTS: Epithelial expression of COX-2 protein was detected in 75% (15/20) of benign cases, 83% (10/12) of cases with LGD, and 100% of cases with HGD or adenocarcinoma. Using a semiquantitative analysis, median staining scores for the groups were 2, 3, 14, and 13, respectively (scale 0-16), with the expression being significantly higher in the HGD and cancer groups compared to benign and LGD groups (p < 0.001). CONCLUSIONS: This study demonstrates clear COX-2 expression in the epithelial cells in Barrett's metaplasia, confirms elevated expression in adenocarcinoma, and shows that the elevation in expression occurs in the progression from LGD to HGD.     

Cyclooxygenase－2 expression and angiogenesis in colorectal cancer

AIM: Cyclooxygenase-2 is involved in a variety of important cellular functions, including cell growth and differentiation,cancer cell motility and invasion, angiogenesis and immune function. However, the role of cyclooxygenase-2 as an angiogenic factor in colorectal cancer tissue is still unclear.We investigated the relationship between cyclooxygenase2 and angiogenesis by analyzing the expression of cyclooxygenase-2 in colorectal cancer tissue, as well as its association with vascular endothelial growth factor (VEGF)and microvascular density (MVD). METHODS: The expression of cydooxygenase-2, VEGF, as well as MVD was detected in 128 cases of colorectal cancer by immunohistochemical staining. The relationship between the cydooxygenase-2 and VEGF expression and MlVD was evaluated.Our objective was to determine the effect of cyclooxygenase2 on the angiogenesis of colorectal cancer tissue. RESULTS: Among 128 cases of colorectal cancer, 87 were positive for cyclooxygenase-2 (67.9 %), and 49 for VEGF (38.3 %), respectively. The microvessel counts ranged from 23 to 142, with a mean of 51.7 (standard deviation, 19.8). The expression of cydooxygenase-2 was correlated significantly with the depth of invasion, stage of disease, metastasis (lymph node and liver), VEGF expression and MlVD. Patients in T3-T4, stage Ⅲ-ⅣV and with metastasis had much higher expression of cydooxygenase-2 than patients in T1-T2, stage Ⅰ-Ⅱ and without metastasis (P＜0.05). The positive expression rate of VEGF (81.6 %) in the cyclooxygenase-2 positive group was higher than that in the cyclooxygenase-2 negative group (18.4 %,P＜0.05). Also, the microvessel count (56±16) in cyclooxygenase-2 positive group was significantly higher than that in cyclooxygenase-2 negative group (43±12, P＜0.05). The microvessel count in tumors with positive cyclooxygenase-2and VEGF was the highest (60±18, 41-142, P＜0.05), whereas that in tumors with negative cyclooxygenase-2 and VEGF wasthe lowest (39±16, 23-68, P＜0.05). CONCLUSION: Cyclooxygenase-2 may be associated with tumor progression by madulating the angiogenesis in colorectal cancer tissue and used as a possible biomarker.     

Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets

Cyclooxygenase (COX)-1 or -2 and prostaglandin (PG) synthases catalyze the formation of various PGs and thromboxane (TX) A(2). We have investigated the expression and activity of COX-1 and -2 during human megakaryocytopoiesis. We analyzed megakaryocytes from bone marrow biopsies and derived from thrombopoietin-treated CD34(+) hemopoietic progenitor cells in culture. Platelets were obtained from healthy donors and patients with high platelet regeneration because of immune thrombocytopenia or peripheral blood stem cell transplantation. By immunocytochemistry, COX-1 was observed in CD34(+) cells and in megakaryocytes at each stage of maturation, whereas COX-2 was induced after 6 days of culture, and remained detectable in mature megakaryocytes. CD34(+) cells synthesized more PGE(2) than TXB(2) (214 +/- 50 vs. 30 +/- 10 pg/10(6) cells), whereas the reverse was true in mature megakaryocytes (TXB(2) 8,440 +/- 2,500 vs. PGE(2) 906 +/- 161 pg/10(6) cells). By immunostaining, COX-2 was observed in <10% of circulating platelets from healthy controls, whereas up to 60% of COX-2-positive platelets were found in patients. A selective COX-2 inhibitor reduced platelet production of both PGE(2) and TXB(2) to a significantly greater extent in patients than in healthy subjects. Finally, we found that COX-2 and the inducible PGE-synthase were coexpressed in mature megakaryocytes and in platelets. We conclude that both COX-isoforms contribute to prostanoid formation during human megakaryocytopoiesis and that COX-2-derived PGE(2) and TXA(2) may play an unrecognized role in inflammatory and hemostatic responses in clinical syndromes associated with high platelet turnover.     

Uteroglobin-related protein 1 expression suppresses allergic airway inflammation in mice

RATIONALE: Uteroglobin-related protein (UGRP) 1, which is highly expressed in the epithelial cells of the airways, has been suggested to play a role in lung inflammation. OBJECTIVES: The aim of study was to understand the effect of overexpressed UGRP1 on lung inflammation in a mouse model of allergic airway inflammation. METHODS: Ovalbumin-sensitized and -challenged mice, a model for allergic airway inflammation, were used in conjunction with recombinant adenovirus expressing UGRP1. MEASUREMENTS AND MAIN RESULTS: We demonstrated that intranasal administration of adeno-UGRP1 successfully delivered UGRP1 to the epithelial cells of airways and markedly reduced the number of infiltrating inflammatory cells, particularly eosinophils, in lung tissue as well as the level of proinflammatory cytokines such as interleukin (IL)-4, IL-5, and IL-13 in bronchoalveolar lavage fluids. The healed phase of inflammation was clearly seen in the peripheral areas of adeno-UGRP1-treated mouse lungs. CONCLUSION: These results demonstrate that UGRP1 can suppress inflammation in the mouse model of allergic airway inflammation. Based on this result, we propose UGRP1 as a novel therapeutic candidate for treating lung inflammation such as is found in asthma.     

Cyclooxygenase-2 expression on ifosfamide-induced hemorrhagic cystitis in rats

Purpose Hemorrhagic cystitis (HC) is a limiting side effect of chemotherapy with ifosfamide (IFS). In this study, we investigated the participation of cyclooxygenase-2 (COX-2) upon ifosfamide-induced HC. Methods Male Wistar rats (150–200 g; six rats per group) were treated with saline, IFS (400 mg/kg, i.p.) and analyzed by changes in bladder wet weight, macroscopic and microscopic parameters, and COX-2 expression. In other groups etoricoxib (selective COX-2 inhibitor), indomethacin (non-selective COX inhibitor), thalidomide (selective TNF-α inhibitor), pentoxifyllin (non-selective TNF-α inhibitor) were added 1 h before IFS administration. The classical protocol using three doses of Mesna was also evaluated and compared with two extra doses of etoricoxib or indomethacin. Results COX-2 was expressed significantly 24 h after IFS administration mainly in myofibroblasts and mast cells evaluated by immunohistochemistry. Treatment 1 h before IFS injection with etoricoxib, indomethacin, thalidomide, and pentoxifylline reduced COX-2 expression and some macroscopic and microscopic parameters in IFS-induced HC. Moreover, addition of etoricoxib or indomethacin with the last two doses of Mesna was more efficient than three doses of Mesna alone when evaluated microscopically. Conclusions COX-2 participates in the pathogenesis of IFS-induced HC and the treatment with COX and TNF-α inhibitors reduced COX-2 expression. The addition of COX-inhibitors to the last two doses of Mesna represents a new therapeutic strategy of preventing HC.     

A gene-dosage effect for interleukin-4 receptor alpha-chain expression has an impact on Th2-mediated allergic inflammation during bronchopulmonary mycosis

Interleukin (IL)-4 and IL-13 are key factors in the pathogenesis of bronchopulmonary mycosis induced in mice by infection with Cryptococcus neoformans. Both cytokines use the IL-4 receptor alpha-chain (IL-4Ralpha). In this study, we investigated the role played by IL-4Ralpha expression in susceptibility to pulmonary C. neoformans infection. IL-4Ralpha(-/-) mice were extremely resistant. To characterize the effect of IL-4Ralpha expression level on disease outcome, we generated IL-4Ralpha(+/-) first-generation (F1) mice. IL-4Ralpha(+/-) mice showed intermediate levels of IL-4Ralpha expression, in contrast to higher levels in wild-type mice and no expression in IL-4Ralpha(-/-) mice, indicating biallelic expression of the gene for IL-4Ralpha (Il4ra). Concomitant with intermediate IL-4Ralpha expression, F1 mice showed intermediate susceptibility associated with altered Th2/Th17 cytokine production, decreased immunoglobulin E levels, and reduced allergic inflammation. This indicates a gene-dosage effect of IL-4Ralpha expression on susceptibility to bronchopulmonary mycosis. These data provide the basis for novel therapies antagonizing IL-4Ralpha in Th2-related pulmonary infection and possibly also in asthma.     

Cyclooxygenase-2 expression in squamous cell carcinoma of the esophagus

Increased cyclooxygenase-2 expression has been reported to be a poor prognostic indicator in a number of cancers. In this study we investigated the relationship between COX-2 expression in squamous cell carcinoma of the esophagus and tumor characteristics and patient survival. The study group consisted of 90 men and 48 women who underwent esophagectomy for squamous cell carcinoma of the esophagus between October 1984 and May 1985. COX-2 expression was measured by immunohistochemistry in 138 primary cancers, 23 metastatic lymph nodes and 21 normal esophageal stumps. The relationship between the extent of staining for COX-2 and clinicopathological features and survival was determined. The extent of staining for COX-2 in both primary and metastatic cancers was higher than in normal squamous epithelia (P = 0.002 and P < 0.0001 respectively), and the grade of staining in the primary tumor correlated positively with the finding of lymph node metastases (P = 0.03). The 5-year survival rate in patients with less than 10% COX-2 positive cells was 47.5% compared to 23.2% in patients with more than 10% COX-2 positive cells (P = 0.0036). The relationship between survival and COX-2 staining was not due to COX-2 being a surrogate marker for TNM stage. Our results show that the expression of COX-2 is elevated in squamous cell carcinoma of the esophagus compared to normal epithelium and correlates with lymph node metastases. Survival was longer in those patients whose tumors expressed lower levels of COX-2.