消化系肿瘤发生中COX-2基因的表观遗传修饰研究

环氧合酶-2(COX-2)是COX的同工酶之-，呈诱导性表达，即在正常生理状态下，多数组织不表达，而当受到相应刺激后，其表达迅速上调。COX-2的过度生成在消化系肿瘤的发生中起重要作用，然而，现已在-些肿瘤中发现COX-2的低生成。现就近年来COX-2基因在消化系肿瘤中的表观遗传修饰研究作-综述。     

环氧合酶-2抑制剂防治消化系统肿瘤研究进展

大量研究表明，环氧合酶(COX)-2过度表达与消化系肿瘤的发生、发展密切相关。COX-2抑制剂已成功用于结肠癌的化学预防。近年来，COX-2抑制剂及其在消化系肿瘤防治中的应用以及其抗肿瘤作用的分子机制等方面的研究取得不少进展，现综述如下。     

丹皮酚和塞来昔布对大肠癌细胞环氧合酶-2和P27蛋白表达的影响

研究表明，诱导环氧合酶-2（COX-2）异常表达对消化系肿瘤的发生和演化具有重要的促进作用。COX-2特异性抑制剂塞来昔布可在一定程度上有效预防大肠癌，减少大肠癌发病率，但长期应用可带来一系列心血管不良反应。因此有必要进一步探讨用于大肠癌防治的不良反应小、安全有效的COX-2抑制剂。     

bFGF、COX-2研究进展及与胃癌的关系

碱性成纤维细胞生长因子(bFGF)是存在于细胞质中的血管生成因子,可以通过自分泌或旁分泌方式参与肿瘤间质血管生成的调节,促进细胞迁移、有丝分裂和增殖.对肿瘤的发生、发展及预后均产生影响.环氧合酶-2(COX-2)是合成前列腺素的关键酶之一,其在组织中呈诱导性表达,与肿瘤浸润转移有一定的相关性.研究表明,COX-2表达在肿瘤尤其是消化系肿瘤的发生、发展、分化和转移中起重要作用.在胃癌中,bFGF与COX-2均存在特异性高表达.     

重视环氧合酶—2与消化系肿瘤关系的研究

环氧合酶（cyclooxygenas,COX）是催化花生四烯酸转化为前列腺素（PGs）的关键酶,有COX－1和COX－2两种异构酶。COX－1存在于大多数细胞和组织中,产生具有重要生理作用的PGs,在胃肠道具有细胞保护作用;相反,COX-2在许多组织中几乎不能测得,在组织损伤、炎症或细胞恶性转化时表达增强。COX－1和COX-2的生物活性均能被阿司匹林和其他非好甾体类抗炎药（NSAIDS）所抑制,而选择性COX-2抑制剂N4主要抑制COX－2。410年来大量研究表明,COX-2的过度表达与肿瘤,特别是消化系肿瘤的发生、发展密切相关,现就这方面的研究进…     

大肠肿瘤COX-2、VEGF和MVD的表达及其意义

目的探讨环氧合酶-2（COX-2）与肿瘤的血管生成、转移、细胞增殖,病理类型、患者预后的关系,深入研究COX-2选择性抑制剂对大肠肿瘤防治的作用机制,方法采用免疫组化方法检测大肠肿瘤中COX-2、血管内皮生长;因子（WXGF）、CD34、增殖细胞核抗原（PCNA）的表达情况。结果COX-2和VEGF的表达在大肠癌均有显著增加,分别为78％和76％。大肠癌中COX-2的表达与VEGF的表达相关。COX-2阳性的大肠癌中微血管密度（MVD）是阻性肿瘤中的3．9倍,VEGF阳性的大肠癌中MVD是阻性肿瘤中的3.2位。结论COX-2和VEGF在肠道腺癌和结直肠癌形成早期就已开始表达,并在腺瘤的增生、癌变,肿瘤的形成、生长和血管形成中起重要作用。     

RUNX3与消化系肿瘤的关系

消化系肿瘤在常见的恶性肿瘤中占有很高的比重,发病率逐年上升并且年龄趋于年轻化,对消化系肿瘤的研究也更加广泛和深入。RUNX 3基因作为抑癌基因首次是在胃癌中发现的,后来在其它多种恶性肿瘤中也均有发现,并且在多种肿瘤中还发现了RUNX 3的高甲基化和杂合性缺失。本文现就RUNX3基因与消化系肿瘤的关系做一浅述。 1 RUNX3基因的概述     

糖尿病与消化系肿瘤关系的研究进展

近年来,随着对消化系肿瘤研究的不断深入,糖尿病与消化系肿瘤的关系越来越受到学者们的关注。目前国外大量流行病学调查研究表明:糖尿病患者消化系肿瘤(包括结直肠癌、胰腺癌、原发性肝癌等)的发病率明显增加。2型糖尿病诱发消化系统肿瘤的可能机制包括:(1)胰岛素样生长因子1的作用;(2)高胰岛素血症和胰岛素抵抗的作用;(3)宿主免疫功能紊乱;(4)长期高血糖的作用;(5)遗传因素和致癌因素长期作用及微量元素失衡等多方面因素协同作用。     

PI3K/Akt和COX-2信号通路阻断在胃癌治疗中的应用

磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/PKB,PI3K/Akt)和环氧合酶-2(COX-2)信号通路的异常改变在肿瘤的发生、发展过程中起重要作用. 并且可以引起肿瘤的一系列生物学行为改变, 对肿瘤患者的治疗和预后产生很大影响. 本文研究PI3K/Akt和COX-2信号通路阻断及其机制, 为包括胃癌在内的多种肿瘤的分子靶向治疗提供新的方向.     

NS-398对HepG2细胞的放射增敏作用及其机制

有研究显示环氧合酶-2(COX-2)在许多肿瘤中高表达,推测与肿瘤的发生、发展、转移密切相关.研究还发现抑制COX-2的表达和(或)对抗COX-2的活性可以阻滞COX-2的促癌作用[1],提示COX-2可能成为肿瘤诊治的一个新靶点.本研究采用COX-2选择性抑制剂NS-398处理人肝癌细胞株HepG2细胞,旨在探讨其对肝癌放射敏感性的影响及其可能作用机制.     

Cyclooxygenase-2 expression is associated with well-differentiated and intestinal-type pathways in gastric carcinogenesis

BACKGROUND/AIMS: Cyclooxygenase-2 (COX-2) expression appears to be increased in several different types of human cancers, suggesting that the presence of COX-2 is associated with carcinogenesis. Recently, increased expression of COX-2 has been frequently detected in gastric cancer, and this may have prognostic significance. In the present study, we aimed to analyze the expression of COX-2 in a much larger sample to determine whether COX-2 expression is related to the clinicopathological features and survival rates of patients with gastric cancer. METHODS: We investigated 140 patients with gastric cancer who underwent surgery between January 1992 and December 1993 and examined the expression of COX-2 in human gastric cancer tissue by immunohistochemistry. RESULTS: COX-2 expression was present in the cytoplasm of tumor cells but not in normal gastric epithelia. Positive expression of COX-2 was detected in 86 of 140 gastric cancers analyzed (61.4%). Positive expression of COX-2 correlated with the depth of tumor invasion (p = 0.015). However, there was no association between COX-2 expression and tumor stage or status of lymph node or distant metastasis. Furthermore, COX-2 expression was not associated with patient survival (p = 0.816). Positive expression of COX-2 occurred more frequently in intestinal than in diffuse or mixed types of cancer and correlated with tumor differentiation (p < 0.001, p = 0.001, respectively). CONCLUSION: These results suggest that COX-2 may play an important role in the evolution of gastric carcinogenesis and be associated with well-differentiated and intestinal type pathways in gastric carcinogenesis. However, COX-2 expression seems to be less useful for establishing prognosis for gastric cancer.     

Expression of cyclooxygenase-2 and epidermal growth factor receptor in primary and recurrent glioblastoma multiforme

Purpose: To investigate the pattern and level of cyclooxygenase-2 (COX-2) expression in a series of high grade primary and recurrent glioblastoma multiforme (GBM) and correlation with time to recurrence and patients’ survival following therapy. The relationship between COX-2 and epidermal growth factor receptor (EGFR) immunoreactivities was evaluated. Materials and methods: Specimens of 14 primary and 14 recurrent GBMs (eight pairs) following surgery and full course radiation therapy were processed for immunostaining on COX-2 and EGFR. Tumor cell positivity was semi-quantitatively scored. COX-2 scores of the primary tumor and recurrence were correlated with the time to radiological tumor progression and patients’ survival. Results: COX-2 positive tumor cells were disseminated throughout the tumor parenchyma. The intensity and pattern of COX-2 expression were heterogeneous, with predominant expression in areas surrounding tumor necrosis. Scoring of COX-2 positivity revealed values between 1 and 80% of the cells. Primary GBMs with COX-2 expression levels between 25% and 70% of the tumor cells showed a shorter time to radiological recurrence than GBMs with <10% COX-2 positive tumor cells (respectively, 219±50 and 382±77 days). No correlation was found between the COX-2 expression in the primary tumor and patients’ survival (r _s=−0.073) following therapy. No correlation was found either between COX-2 and EGFR immunoreactivity. Conclusions: Immunohistochemical expression of COX-2 in GBM showed large variation. Hence, determination of COX-2 expression in tumor specimen for each individual might be relevant for selection of those patients, who could benefit from adjuvant therapy with selective COX-2 inhibitors.     

Role of cyclooxygenase-2 and inducible nitric oxide synthase in pancreatic cancer

BACKGROUND AND AIM: Recently, it has been recognized that both cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) produce important endogenous factors of human tumor progression. However, the clinicopathological and biological significance of the expression of COX-2 and iNOS in pancreatic cancer remains unclear. The objective of this study is to find the possible roles and clinical significance of COX-2 and iNOS expression in pancreatic cancer. METHODS: Seventy-two pancreatic adenocarcinoma tissue specimens were obtained through surgical resection. We investigated the immunohistochemical expression of COX-2 and iNOS in respect to variable clinicopathological characteristics, proliferation activity (by Ki-67 expression), apoptosis (by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling stain), and microvessel density (by CD34 expression; angiogenesis). RESULTS: Immunohistochemical investigations demonstrated immunolabeling of tumor cells with the primary antibodies, bovine anti-iNOS and anti-COX-2 antibodies. The COX-2 and iNOS positive rates were 41.7 and 66.7%, respectively. There was significant correlation between positive COX-2 and positive iNOS expression (P = 0.043). The proliferation index (Ki-67 labeling index) was higher in COX-2 positive specimens compared to COX-2 negative specimen (P = 0.015). The apoptotic index of positive iNOS expressions was significantly higher than negative expressions (P < 0.001). The expression of COX-2 and iNOS proteins did not correlate with age, sex, serum bilirubin, CA-19-9, location, size, American Joint Committee on Cancer stage, differentiation, distant metastasis, patient survival, or microvessel density. CONCLUSIONS: Although the pattern of positive expression was similar in both enzymes, the effect on tumor progression differed; iNOS expression may play a role in apoptosis of tumor cell, while COX-2 expression may contribute to tumor proliferation. However, COX-2 and iNOS expression is not related to prognosis in patients with pancreatic cancer.     

Tumor cyclooxygenase-2 levels correlate with tumor invasiveness in human hepatocellular carcinoma

ABM: Recent studies suggested that cyclooxygenase-2 (COX-2) enhances tumor angiogenesis via upregulation of vascular endothelial growth factor (VEGF). Although COX-2 expression has been demonstrated in hepatocellular carcinoma (HCC), the significance of COX-2 in progression of HCC remains unclear. This study evaluated the clinico-pathological correlation of COX-2 level and its relationship with VEGF level in HCC. METHODS: Fresh tumor tissues were obtained from 100 patients who underwent resection of HCC. COX-2 protein expression was examined by immunohistochemistry, and quantitatively by an enzyme immunometric assay (EIA) of tumor cytosolic COX-2 levels. Tumor cytosolic VEGF levels were measured by an ELISA. RESULTS: Immunostaining showed expression of COX-2 in tumor cells. Tumor cytosolic COX-2 levels correlated with VEGF levels (r = 0.469,P<0.001). Correlation with clinicopathological features showed significantly higher tumor cytosolic COX-2 levels in the presence of multiple tumors (P = 0.027), venous invasion (P = 0.030), microsatellite lesions (P=0.037) and advanced tumor stage (P = 0.008). Higher tumor cytosolic COX-2 levels were associated with worse patient survival. CONCLUSION: This study shows that elevated tumor COX-2 levels correlate with elevated VEGF levels and invasiveness in HCC, suggesting that COX-2 plays a significant role in the progression of HCC.     

Leukemic cells modulate induction of COX-2 in human stromal fibroblasts

The interaction of cancer cells with surrounding normal tissue cells is of utmost importance for their survival and tumor progression. For these purposes the cancer cells exploit normal tissue responses associated with inflammation and tissue repair. In the immediate tumor microenvironment one of the early stromal markers is cyclooxygenase-2 (COX-2). In this study we evaluated the effect of leukemia cell lines on nemosis-induced COX-2 expression in stromal fibroblasts. We found that THP-1 cells were the most potent leukemic cells (IC50=746) to suppress COX-2 expression. The U-937 cell line exhibited similar suppressive potency (IC50=921), whereas the KG-1 cell line (IC50=3519) was the least potent to affect COX-2 expression in the stromal cells. Our study shows that human leukemic cells can actively participate in modulation of stromal inflammation via inhibition of COX-2 expression. In a co-culture model of leukemia cell lines and stromal fibroblasts, our data suggest that the tumor-stromal interactions are complexly regulated, and the straightforward association of COX-2 expression with tumor progression may require re-evaluation since some tumor cells, e.g. from hematologic malignancies, may differentially modulate inflammation and COX-2 expression.     

Relationship between expression and distribution of cyclooxygenase-2 and bcl-2 in human gastric adenocarcinoma

AIM: To explore expression and distribution features of COX-2 and bcl-2 in human gastric adenocarcinoma tissues and to study its biological significance. METHODS: Totally 36 human gastric carcinoma samples were enrolled in this study (cardiac adenocarcinoma 16 cases, distal gastric adenocarcinoma 20 cases). The expressions of COX-2 and bcl-2 in cancerous tissues and corresponding para-cancerous tissues were investigated by immunohistochemistry using COX-2 polyclonal antibody and bcl-2 monoclonal antibody. The normal gastric mucosa tissues were used as control. RESULTS: The expressions of COX-2 and bcl-2 in gastric carcinoma were significantly higher than that in the para-cancerous tissues (77.8% vs 47.2%, P<0.01, 80.56% vs 58.33%, P<0.05). The expression of COX-2 in cardiac adenocarcinoma was remarkably higher than that in the distal gastric carcinoma (93.8% vs 65.0%, P<0.01). The expression of COX-2 was mainly localized in the cytoplasm of tumor cells and partly in the nucleus. There is a transition of the COX-2 cytoplasmic positivity to nucleic in tumor cells with the increase of gastric carcinoma pathological grade. Interstitial macrophages, fibroblasts and vascular endothelial cells also expressed COX-2. The tissues with higher expression of COX-2 also expressed high level of bcl-2 protein. CONCLUSION: Abnormal expression pattern of COX-2 within the tissues of human gastric cancer is correlated with tumor location and lymph node metastasis. COX-2 may regulate expression of apoptosis suppressor gene (bcl-2) through interaction of tumor cells and stromal cells and play an important role in the generation and development of tumors, which will be of great help in developing new methods for antitumor therapy.     

Correlation between expression of cyclooxygenase-2 and the presence of inflammatory cells in human primary hepatocellular carcinoma： Possible role in tumor promotion and angiogenesis

AIM: To investigate the association of cyclooxygenase-2 (COX-2) expression with angiogenesis and the number and type of inflammatory cells (macrophages/Kupffer cells; mast cells) within primary hepatocellular carcinoma (HCC) tissues and adjacent non-tumorous (NT) tissues. METHODS: Immunohistochemistry for COX-2, CD34, CD68 and mast cell tryptase (MCT) was performed on 14 well-characterized series of liver-cirrhosis-associated HCC patients. COX-2 expression and the number of inflammatory cells in tumor lesions and surrounding liver tissues of each specimen were compared. Moreover, COX-2, CD34 staining and the number of inflammatory cells in areas with different histological degrees within each tumor sample were comparatively analyzed. RESULTS: The percentage of COX-2 positive cells was significantly higher in NT tissues than in tumors. COX-2 expression was higher in well-differentiated HCC than in poorly-differentiated tissues. Few mast cells were observed within the tumor mass, whereas a higher number was observed in the surrounding tissue, especially in peri-portal spaces of NT tissues. Abundant macrophages/ Kupffer cells were observed in NT tissues, whereas the number of cells was significantly lower in the tumor mass. However, a higher cell number was observed in the well-differentiated tumor and progressively decreased in relation to the differentiation grade. Within the tumor, a positive correlation was found between COX-2 expression and the number of macrophages/Kupffer cells and mast cells. Moreover, there was a positive correlation between CD34 and COX-2 expression in tumor tissues. Comparison between well- and poorly-differentiated HCC showed that the number of CD34-positive cells decreased with dedifferentiation. However, COX-2 was the only independent variable showing a positive correlation with CD34 in a multivariate analysis. CONCLUSION: The presence of inflammatory cells and COX-2 expression in liver tumor suggests a possible relationship with tumor angiogenesis. COX-2 expressing cells and the number of macrophages/Kupffer cells and mast cells decrease with progression of the disease.     

Correlation between expression of cyclooxygenase-2 and the presence of inflammatory cells in human primary hepatocellular carcinoma: Possible role in tumor promotion and angiogenesis

AIM: To investigate the association of cyclooxygenase-2(COX-2) expression with angiogenesis and the number and type of inflammatory cells (macrophages/Kupffer cells;mast cells) within primary hepatocellular carcinoma (HCC)tissues and adjacent non-tumorous (MT) tissues.METHODS: Immunohistochemistry for COX-2, CD34,CD68 and mast cell tryptase (MCT) was performed on 14 well-characterized series of liver-cirrhosis-associated HCC patients. COX-2 expression and the number of inflammatory cells in tumor lesions and surrounding liver tissues of each specimen were compared. Moreover,COX-2, CD34 staining and the number of inflammatory cells in areas with different histological degrees within each tumor sample were comparatively analyzed.RESULTS: The percentage of COX-2 positive cells was significantly higher in NT tissues than in tumors. COX-2 expression was higher in well-differentiated HCC than in poorly-differentiated tissues. Few mast cells were observed within the tumor mass, whereas a higher number was observed in the surrounding tissue, especially in peri-portal spaces of NT tissues. Abundant macrophages/Kupffer cells were observed in NT tissues, whereas the number of cells was significantly lower in the tumor mass.However, a higher cell number was observed in the well-differentiated tumor and progressively decreased in relation to the differentiation grade. Within the tumor, a positive correlation was found between COX-2 expression and the number of macrophages/Kupffer cells and mast cells. Moreover, there was a positive correlation between CD34 and COX-2 expression in tumor tissues. Comparison between well- and poorly-differentiated HCC showed that the number of CD34-positive cells decreased with dedifferentiation. However, COX-2 was the only independent variable showing a positive correlation with CD34 in a multivariate analysis.CONCLUSION: The presence of inflammatory cells and COX-2 expression in liver tumor suggests a possible relationship with tumor angiogenesis. COX-2 expressing cells and the number of macrophages/Kupffer cells and mast cells decrease with progression of the disease.     

Up-regulation of cyclooxygenase 2 gene expression correlates with tumor angiogenesis in human colorectal cancer.

BACKGROUND & AIMS: Recent studies have shown that cyclooxygenase (COX)-2 and its products, prostaglandins (PGs), may be involved in colorectal carcinogenesis. The aim of this study was to determine whether COX-2 expression and PGE(2) production correlate with microvessel density, vascular endothelial growth factor (VEGF) expression, and tumor metastasis in human colorectal cancer. METHODS: Tumor samples and adjacent normal mucosa were obtained from 31 surgical specimens. Immunohistochemical expression of COX-2, VEGF, and CD31 was analyzed on paraffin-embedded tissue sections. COX-2 and COX-1 proteins were determined by Western blot analysis. COX-2 and VEGF messenger RNA expressions were evaluated using Northern blot analysis. PGE(2) production was determined by specific radioimmunoassay. RESULTS: The immunohistochemical expressions of both COX-2 and VEGF were significantly correlated with microvessel density (P = 0.02 and P = 0.002, respectively). A significant correlation was found between COX-2 and VEGF expression (P = 0.004). Western analysis confirmed the up-regulation of COX-2 protein expression. COX-2 and VEGF genes were overexpressed in tumor specimens as compared with normal mucosa. PGE(2) levels were significantly higher in metastatic tumors than in nonmetastatic ones (P = 0.03). CONCLUSIONS: COX-2 is related to tumor angiogenesis in colorectal cancer. It is likely that VEGF is one of the most important mediators of the COX-2 angiogenic pathway.     

Cyclooxygenase-2 expression as a predictor of outcome in colorectal carcinoma

AIM: To correlate cyclooxygenase-2 (COX-2) expression profile with clinical and pathological variables to assess their prognostic/predictive value in colorectal carcinoma (CRC).METHODS: Archival tumor samples were analyzed using immunohistochemistry for COX-2 expression in 94 patients with CRC. Patients were diagnosed and treated at the Departments of Surgery and Oncology, King Abdulaziz University Hospital, Saudi Arabia.RESULTS: Fifty-six percent of the tumors showed positive cytoplasmic COX-2 expression, whereas 44% of cases were completely COX-2-negative. There were no significant correlations between COX-2 expression and sex, age, grade or tumor location. However, COX-2 expression revealed a significant correlation with tumor stage (P = 0.01) and distant metastasis (P = 0.02), and a borderline association with lymph node involvement (P = 0.07). Tumors with high COX-2 expression showed a higher recurrence rate than tumors with no expression (P < 0.009). In univariate Kaplan-Meier survival analysis, there was a significant (P = 0.026) difference in disease-free survival between COX-2-positive and negative tumors in favor of the latter. COX-2 expression did not significantly predict disease-specific survival, which was much shorter for COX-2-positive tumors. In multivariate (COX) models, COX-2 did not appear among the independent predictors of disease-free survival or disease-specific survival.CONCLUSION: COX-2 expression seems to provide useful prognostic information in CRC, while predicting the patients at high risk for recurrent disease.