COX-2基因单核苷酸多态性与结直肠腺瘤遗传易感性的关系

目的 探讨环氧合酶-2(COX-2)基因多态性与结直肠腺瘤(CRA)易感性的关系.方法 采用病例对照研究方法,应用聚合酶链反应-限制性片段长度多态性技术(PCR-RFLP)和错配聚合酶链反应-限制性片段长度多态性技术(PIRA-PCR),分别检测110例CRA患者和120名健康人群的COX-2基因-765G＞C、-1195G＞A、8473T＞C 3个多态位点,采用x2检验比较不同基因型与CRA易感性的关系.结果 CRA组和对照组的COX-2-765 G＞C、-1195G＞A 2个位点的3种基因型频率分布差异无统计学意义(P=0.972,P=0.313);两组间COX-2 8473T＞C位点的3种基因型分布差异有统计学意义(P=0.034),Logistic回归分析显示,携带突变等位基因C的个体(8473TC+CC) CRA的易感性显著降低(OR=0.500,95 ％CI:0.274-0.913,P=0.024).结论 COX-2-765G＞C、-1195G＞A可能与CRA易感性无关,COX-2 8473T＞C与CRA易感性相关.     

COX-1、COX-2在小剂量阿司匹林相关性胃黏膜病变中的表达和意义

背景:阿司匹林系非甾体消炎药(NSAIDs)的代表药物,长期或过量服用可导致胃黏膜损伤。目前对于阿司匹林损伤胃黏膜的机制尚存在争议。目的:探讨环氧合酶(COX)-1、COX-2在阿司匹林相关性胃黏膜病变中的表达和意义。方法:选取2008年12月～2011年1月于清华大学第一附属医院诊断为小剂量阿司匹林相关性胃黏膜病变的患者136例,根据其胃镜下表现分为出血组、溃疡组、胃炎组,选取8例同期健康体检者作为正常对照组。应用免疫组化方法检测入选者胃黏膜组织中的COX-1、COX-2表达。结果:COX-1在正常对照组、胃炎组、溃疡组、出血组胃黏膜组织中的免疫组化评分(IHCS)逐渐降低,分别为7.75±3.62、1.76±1.05、1.33±0.79、1.08±0.65,各组间差异有统计学意义(P<0.05)。COX-2在正常对照组、胃炎组、溃疡组、出血组胃黏膜组织中的IHCS分别为7.50±3.34、7.30±2.15、7.28±2.72、7.33±3.17,各组间差异无统计学意义(P>0.05)。结论:小剂量阿司匹林是通过抑制COX-1途径而非COX-2途径导致胃黏膜损伤。     

COX-2单核苷酸多态(SNP)与结直肠肿瘤遗传易感性关系的研究进展

环氧合酶-2(COX-2)是前列腺素(PG)合成过程中的关键酶之一,参与机体的多种病理生理过程,如炎性反应、发热、出凝血机制、肿瘤形成等.COX-2基因(PTGS2)被认为是一个非常重要的肿瘤相关基因,PTGS2具有多态性.近年来国内外开展了大量COX-2单核苷酸多态(SNP)与结直肠肿瘤遗传易感性的病例对照研究,现将其研究进展做一综述.     

5-LOX mRNA和COX-2 mRNA在结直肠癌中的表达及二者的相互关系

目的 研究5脂氧合酶(5-LOX)和环氧合酶2(COX-2)在结直肠癌中的表达及二者的相互关系.方法 用RT-PCR检测39例结直肠癌标本中5-LOX mRNA和COX-2 mRNA的表达.结果 5-LOX mRNA和COX-2 mRNA在结直肠癌组织中的表达率分别为84.6%(33/39)及76.9%(30/39),均与结直肠癌临床分期、肿瘤大小、肿瘤分化程度有关.但两者无相关性(P＞0.05).结论 5-LOX mRNA和COX-2 mRNA在结直肠癌组织中表达增高,提示了在研究结直肠癌治疗和预防时可采取对代谢途径抑制这一新方向.     

TGF-β1及Smad4在结直肠腺瘤癌变过程中的表达及意义

目的探讨TGF-β1和Smad4在结直肠腺瘤癌变发生、发展中的作用。方法采用RT-PCR和免疫组化法分别检测30例结直肠腺癌、28例结直肠腺瘤和20例正常结直肠黏膜组织中TGF-β1、Smad4的mRNA和蛋白表达情况。结果结直肠腺癌组织中TGF-β1mRNA、蛋白明显高于而Smad4 mRNA、蛋白表达均明显低于结直肠腺瘤组织和正常大肠黏膜组织（P均〈0.01）;TGF-β1 mRNA与Smad4 mRNA表达呈明显负相关（r=-0.5,P〈0.05）。结论 TGF-β1、Smad4均参与了结直肠腺瘤的癌变过程,Smad4低表达通过负反馈作用使TGF-β1表达增加。     

COX-2、EGFR和Ki67在大肠癌组织中的表达及其意义

目的 探讨环氧合酶-2(COX-2)、表皮生长因子受体(EGFR)和Ki67在大肠癌组织中的表达及其意义.方法 选取大肠癌70例、大肠腺瘤21例和正常大肠组织15例,采用免疫组织化学Envision方法检测COX-2、EGFR和Ki67的表达.结果 在正常大肠黏膜、大肠腺瘤和大肠癌组织中,COX-2的阳性表达率分别为33.3%、71.4%和80.0%,大肠癌和腺瘤组显著高于正常组(P均＜0.05);EGFR的阳性表达率依次为0、23.8%和65.7%,两两比较有统计学差异(P均＜0.05);Ki67的阳性表达率依次为40.0%、76.2%和82.8%,大肠癌和腺瘤组织中的表达均高于正常大肠组织(P均＜0.05).COX-2在有淋巴结转移的大肠癌组中的表达明显高于无淋巴结转移组(P＜0.05);EGFR在低分化、高分期和有淋巴结转移大肠癌中的表达明显增强(P均＜0.05),且COX-2与EG-FR、COX-2与Ki67、EGFR与Ki67之间均具有相关性(r=0.316,0.435,0.314,P均＜0.05).结论 COX-2、EGFR和Ki67对大肠癌的发生、发展有协同作用.     

脂类代谢与结直肠腺瘤

脂类代谢异常与结直肠腺瘤的发生和恶变之间存在必然的联系,大量研究表明脂类、脂类代谢产物及参与其代谢的酶可能是结直肠腺瘤发生和恶变的独立危险因素。     

15-PGDH和COX-2在大肠腺癌中的表达

目的研究NAD+依赖性15-羟基前列腺素脱氢酶(15-PGDH)和环氧合酶-2(Cycboxygenase-2,COX-2)在大肠腺癌组织、大肠腺瘤组织及正常大肠组织中的表达,探讨两者在大肠腺癌组织中的表达情况及其与大肠腺癌临床病理因素的关系。方法应用免疫组织化学(SABC)法检测40例大肠腺癌组织、20例大肠腺瘤组织和20例正常大肠组织中15-PGDH及COX-2的表达情况。结果15-PGDH在大肠腺癌(15%)和腺瘤组织中(20%)的阳性表达率显著低于正常大肠组织(100%)(P0.01),在大肠腺癌和腺瘤中15-PGDH的表达差异无统计学意义(P0.05)。15-PGDH蛋白表达与大肠腺癌患者的性别、年龄、分化程度及Dukes分期和有无淋巴结转移等临床病理参数均无关(P0.05)。COX-2在大肠癌组织(80%)和大肠腺瘤组织中(70%)的表达明显高于正常大肠组织(25%)(P0.01)。且其在大肠癌中的阳性表达率随大肠癌Dukes分期的升高、病理分化程度的降低及远处淋巴结的转移而逐渐增高(P0.05)。大肠癌组织中15-PGDH和COX-2的表达呈负相关(r=-0.544,P=0.000)。结论大肠腺癌组织中15-PGDH的表达缺失或减少可能发生在大肠腺癌发生、发展的早期,是大肠腺癌发生的抑制剂。大肠腺癌组织中COX-2的表达明显增高,其表达的增加可能促进了大肠癌的发生、发展。     

RTP801基因在结直肠癌和结直肠腺瘤中的表达及其临床意义

RTP801（hypoxia—inducible factor 1-responsive gene,RTP801）最初是作为低氧诱导因子一l（hypoxia—inducible fac-tor-1,HIF-1）的应答基因被发现的,缺氧可诱导其表达急剧升高。最近我们通过研究发现,     

COX-2、15-PGDH在结直息肉组织中的表达及其作用

目的:探讨环氧合酶-2(COX-2)和15-羟基前列腺素脱氢酶(15-PGDH)在结直肠息肉组织中的表达及在息肉恶变中的作用.方法:选取2009-02/2009-10肠镜下摘除的结直腺瘤性息肉48例及增生性息肉25例,活检或外科手术的结直肠腺癌15例及正常结肠黏膜15例作为对照.采用RT-PCR和Western blo...     

Bcl-2与PCNA在大肠腺瘤和大肠癌中的表达

目的　探讨增殖细胞核抗原 (proliferatingcellnuclearantigen ,PCNA)与原癌基因bcl 2在大肠腺瘤和大肠癌中的表达变化以及与大肠腺瘤和大肠癌的发生、发展的关系。方法　采用免疫组化S P法 ,分别检测PCNA与bcl 2在 18例大肠腺瘤和 18例大肠癌中的表达。结果　PCNA在大肠腺瘤和大肠癌中的标记指数分别为 65 95± 12 94%和 84 5 3± 10 3 9% ,两者均明显高于正常肠粘膜中的指数 ,P <0 0 0 1,两者相比有显著性差异 ,P <0 0 1。Bcl 2在大肠腺瘤和大肠癌中的表达分别为 81 10± 10 0 0 %和 65 78±12 95 % ,两者均明显高于正常肠粘膜中的表达P <0 0 0 1。两者相比有显著性差异 ,P <0 0 1。结论　大肠癌的癌前病变腺瘤中存在活跃的细胞增殖 ,而且同时有细胞凋亡的改变 ,细胞增殖和细胞凋亡的调控失常共同导致了肿瘤的发生。     

COX-2及survivin在涎腺多形性腺瘤中表达的定量研究

目的　探讨环氧合酶- 2 (COX- 2 )及生存素(survivin)在良、恶性涎腺多形性腺瘤中的表达及其与肿瘤发生发展的关系。方法　采用流式细胞技术检测5 0例良性、17例恶性涎腺多形性腺瘤组织中COX- 2与survivin的表达,并与10例正常腮腺组织进行对比分析。结果　良、恶性涎腺多形性腺瘤及正常腮腺组织COX- 2的阳性表达率分别为76 %、10 0 %、0 ,其荧光指数(FI)分别为1.79±0 .12、3.0 1±0 .4 0、0 .82±0 .0 5。survivin阳性表达率分别为5 6 %、10 0 %、0 ,FI分别为1.0 6±0 .5 9、1.85±0 .16、0 .5 6±0 .0 8。各组间COX- 2与survivin表达量有明显差异(P均<0 .0 1)。在17例恶性涎腺多形性腺瘤中COX- 2与survivin的协同表达率为10 0 %。结论　COX- 2与survivin基因与涎腺多形性腺瘤的发生及恶变关系密切。     

大肠癌和大肠腺瘤COX-2和Bcl-2的基因表达及其意义

目的　探讨COX 2及Bcl 2基因在大肠癌和大肠腺瘤组织中的表达及其意义。方法　应用免疫组化ABC法检测 2 8例大肠癌、2 8例大肠腺瘤和 10例正常黏膜中COX 2及Bcl 2表达 ,应用TUNEL法检测细胞凋亡。结果　在大肠癌、大肠腺瘤及正常黏膜中COX 2的阳性表达分别为 82 1%、85 7%和 0 0 %。Bcl 2的阳性表达分别为 75 0 %、78 6%和 2 0 0 %。大肠癌与腺瘤的COX 2及Bcl 2表达均无显著性差异 (P >0 0 5) ,但均显著高于正常黏膜 (P <0 0 1)。大肠癌中凋亡指数明显高于大肠腺瘤 (χ2 =8 80 ,P <0 0 5) ,COX 2和Bcl 2的表达均与大肠腺瘤及大肠癌的细胞凋亡指数呈显著负相关 (腺瘤P <0 0 1;癌P <0 0 5) ,两者均与临床病理特征无相关性 (P >0 0 5) ,大肠癌高、中、低分化各组间及不同Dukles分期 (A、B期和C、D期 )各组间凋亡指数无显著性差异 (P>0 0 5)。结论　COX 2和Bcl 2在大肠腺瘤及大肠癌中表达增强 ,从而抑制了细胞凋亡 ,在大肠腺瘤恶变及大肠癌的发生和发展过程中起到重要作用     

Expression of COX-2 and HER-2 in colorectal cancer and their correlation

AIM: To detect the expression of COX-2 and HER-2 in colorectal cancer and to analyze their correlation and clinical significance.METHODS: A total of 1026 colorectal cancer surgical specimens were collected from patients treated fromDecember 2002 to December 2007 at the First Affiliated Hospital of Anhui Medical University. All specimens were made into 4-μm slices. The expression of COX-2 and HER-2 were detected by immunohistochemistry using the streptavidin-biotin-peroxidase method. The correlations between COX-2 and HER-2 expression and colorectal cancer clinical features were analyzed.RESULTS: The positive rates of COX-2 and HER-2 expression in colorectal cancer were 77.97%(800/1026) and 46.20%(474/1026), respectively. There was a significant correlation between COX-2 and HER-2 expression in colorectal cancer(P 0.05). In patients with tumor size ≥ 5 cm, the positive rates of COX-2 and HER-2 expression were 81.48%(308/378) and 57.94%(219/378), respectively. In patients with serosal invasion, the positive COX-2 and HER-2 expression rates were 80.53%(612/760) and 49.21%(374/760), respectively. In patients with lymph node metastasis, the positive expression rates were 85.04%(506/595) and 54.62%(325/595), respectively, and the positive expression rates differed significantly between patients with lymph node metastasis and those without(P 0.05). In patients with Duke's C and D colorectal cancer, the positive COX-2 and HER-2 expression rates were 82.80%(443/535) and 57.94%(310/535), respectively. In patients with poorly differentiated colorectal cancer, the positive expression rates were 74.49%(210/282) and 52.84%(149/282), respectively(P 0.05). In patients with distant metastasis, the positive expression rates were 82.27%(116/141) and 53.90%(76/141), respectively(P 0.05). These findings suggest that COX-2 and HER-2 have synergistic effects in colorectal cancer. COX-2 and HER-2 expression had no significant correlation with sex, age, or tumor location. CONCLUSION: COX-2 and HER-2 are important markers for invasion and metastasis of colorectal cancer, and they act together to regulate the invasion and metastasis of colorectal cancer.     

Genetic polymorphisms in the cyclooxygenase-1 and cyclooxygenase-2 genes and risk of colorectal adenoma

Purpose  Cyclooxygenase (COX) enzymes, COX1 and COX2, are key in converting arachidonic acid (AA) into prostaglandins that have been associated with colorectal carcinogenesis. The aim of our study was to investigate associations of polymorphisms in COX genes, alone and in interaction with exposures known to be related to inflammation and AA metabolism, with risk of colorectal adenomas. Materials and methods  In a community-, colonoscopy-based case–control study with 162 incident, sporadic colorectal adenoma cases and 211 controls, we investigated associations of two promoter polymorphisms (−842 A  > G in COX1 and −765 G > C in COX2) and two polymorphisms in the 3′-UTR of COX2 (8473 T > C and 9850 A > G) with risk of adenomas. Multiple logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) of colorectal adenoma after adjusting for potential confounders. Results  Overall, there was no evidence for an association between any of the four polymorphisms and colorectal adenomas. However, we found a statistically significant interaction between the COX2 8473 T > C polymorphism and nonsteroidal anti-inflammatory drug (NSAIDs) use (P _interaction = 0.03): The greatest reduced risk was observed for individuals with the 8473 C variant allele who also regularly used NSAIDs (OR = 0.35, 95% CI 0.16–0.75). Conclusion  These results suggest that the C allele of COX2 8473 T > C polymorphism may interact with NSAIDs to reduce risk for colorectal adenoma.     

Cyclooxygenase-2 Expression as a New Marker for Patients with Colorectal Cancer

PURPOSE: Epidemiologic studies indicate that the use of nonsteroidal anti-inflammatory drugs, which inhibit cyclooxygenase activity, reduce the risk of colorectal cancer. In addition, several studies demonstrate increased expression of cyclooxygenase-2 in human colorectal cancer tissues. However, the role of cyclooxygenase-2 expression in colorectal cancer has not yet been fully established. The aim of this study was to clarify the clinicopathologic significance of cyclooxygenase-2 expression in human colorectal cancer. METHODS: A total of 232 surgically resected colorectal cancer specimens were analyzed immunohistochemically with the use of a murine anti-human cyclooxygenase-2 monoclonal antibody. Cyclooxygenase-2 expression was then compared with clinicopathologic background and survival outcome. RESULTS: Cyclooxygenase-2 was expressed in the cytoplasm of the cancer cells but not in normal epithelium. Cyclooxygenase-2 expression was noted in 71.6 percent (166/232) of the cancer patients and correlated significantly with histologic type (P = 0.033), depth of invasion (P = 0.016), pathologic stage (P = 0.020), and metachronous liver metastasis (P = 0.001). Multivariate analysis for factors associated with metachronous liver metastasis showed that cyclooxygenase-2 expression was one of the independent risk factors, second only to lymph node metastasis. Patients with cyclooxygenase-2 expression showed a significantly poorer outcome compared with those without cyclooxygenase-2 expression (P = 0.002). CONCLUSION: Cyclooxygenase-2 expression in the primary lesion may be a useful marker for evaluating prognosis and liver metastasis in patients with colorectal cancer.     

Transforming growth factor beta 1 and metalloproteinase-9 overexpression in colorectal cancer (CC) and adenoma

Background and aims Although the role of transforming growth factor beta (TGFbeta) 1 and metalloproteinase-9 (MMP-9) is well documented in colorectal cancer (CC), there is a little evidence supporting its role in early carcinogenesis. The aim of the study was to determine the pattern of immunohistochemical expression of TGFbeta1, MMP-9, and Ki-67 in CC and adenomatous polyps. Patient/methods The study group comprised 50 patients with colorectal polyps and 33 patients with CC. Endoscopically removed polyps and CC biopsies had been evaluated with histopatologic examination and immunohistochemistry. The biopsies from 30 healthy objects served as a control group. For all antibodies labeling indices (LI) had been calculated. Results Among 62 adenomas, 33 high-grade dysplasia (HGD) and 29 low-grade dysplasia (LGD) had been detected. Mean TGFbeta1, MMP-9, and Ki-67 LI in CC were significantly higher (p < 0.01, 0.01, and 0.01, respectively) than in HGD polyps. Mean TGFbeta1, MMP-9, and Ki-67 LI in HGD polyps were significantly higher than in LGD polyps (p < 0.01, 0.01, and 0.01, respectively). There had been no statistical difference in TGFbeta1, MMP-9, and Ki-67 LI between LGD and the control group (p > 0.05, 0.05, and 0.05, respectively). There was a positive correlation between TGFbeta1 and MMP-9 (r = 0.898), Ki-67 and MMP-9 (r = 0.938), and TGFbeta1 and Ki-67 (r = 0.913). We did not observe any correlation between TGFbeta1, MMP-9, Ki-67 LI and the clinical parameters evaluated. Conclusion The increased expression of TGFbeta1, MMP-9 observed in colorectal adenomas seems to be related to the grade of dysplasia. We assume that overexpression of TGFbeta1, MMP-9 represent an early event in colorectal carcinogenesis and may possibly have the prognostic value.     

大肠癌和大肠腺瘤COX-2和BFGF表达的意义

目的:研究COX-2和BFGF在大肠癌及大肠腺瘤组织中的表达及意义．方法:采用免疫组化SP方法检测了手术切除的大肠癌49例,腺瘤性息肉25例,正常大肠黏膜组织20例中的COX-2和BFGF表达．结果:COX-2和BFGF在大肠癌中的表达阳性率分别为59．2％和69．3％,在腺瘤性息肉的表达率为52．0％和56．0％,COX-2和BFGF在大肠癌组织与腺瘤性息肉中表达无显著性差异(P>0．05):正常肠黏膜中未检出COX-2和BFGF．COX-2和BFGF在大肠癌中表达与性别,年龄,肿瘤大小,肿瘤位置,分化程度无关(P>0．05)．但与肿瘤Dukes分期有关,C,D期高于A,B期(81．5％vs 54．5％,P<0．05),淋巴结转移之间具有显著性差,有异淋巴结转移高于无淋巴结转移(81．5％vs 54．5％,P<0．05)．肠癌组织中COX-2、BFGF表达二者间有相关性(r= 0．349,P<0．05)．结论:COX-2、BFGF在大肠癌组织及大肠腺瘤中的表达水平增高,在大肠腺瘤恶变及大肠癌的发生发展过程中起协同作用,共同促进肿瘤的发生．     

Expression of cyclooxygenase-2 in colorectal cancer and its clinical significance

AIM: To clarify the clinicopathologic significance of COX-2 expression in human colorectal cancer. METHODS: A total of 128 surgically resected colorectal cancer specimens were immunohistochemically analyzed with the use of anti-COX-2, anti-VEGF and anti-MMP-2 antibodies. The relationship between the cyclooxygenase-2 expression in primary lesions of colorectal cancer and clinicopathoiogic parameters was evaluated by chi-square test. RESULTS: Among 128 cases of colorectal cancer, 87 (67.9%) were positive for cyclooxygenase-2. The expression of cyclooxygenase-2 was significantly correlated with the depth of invasion, stage of disease, and metastasis (lymph node and liver). Patients in T3-T4, stages Ⅲ-Ⅳand with metastasis had much higher expression of cyclooxygenase-2 than ones in T1-T2, stages Ⅰ-Ⅱ and without metastasis (P<0.05). Among 45 cases of colorectal cancer with lymph node metastasis, the COX-2-positive rate was 86.7% (39/45) for primary lesions and diffuse cytoplasmic staining for COX-2 protein was detected in cancer cells in 100% of metastatic lesions of the lymph nodes. VEGF expression was detected in 49 tumors (38.3%), and VEGF expression was closely correlated with COX-2 expression. 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). MMP-2 expression was detected in 88 tumors (68.8%), and MMP-2 expression was closely correlated with COX-2 expression. The positive expression rate of MMP-2 (79.6%) in the positive COX-2 group was higher than that in the negative COX-2 group (20.4%, P<0.05). CONCLUSION: Cyclooxygenase-2 may be associated with tumor progression by modulating the angiogenesis and cancer cell motility and invasive potential in colorectal cancer and it can be used as a possible biomarker.     

环氧化酶-2基因启动子区多态性与结直肠癌的易感性

目的:探讨环氧化酶-2(cyclooxygenase-2,COX-2)基因启动子区的-1195(G/A,rs689466)及3’非翻译区的8473(T/C,rs5275)2个位点的基因多态性与结直肠癌(colorectal cancer,CRC)发病风险的相关性.方法:采用病例-对照研究,利用聚合酶链式反应和限制性片段长度多态性(polymerase chain reaction-restrictive fragment length polymorphism,PCR-RFLP)分析方法,对343例CRC患者和340例健康人的COX-2基因的2个位点的多态性进行检测,采用SPSS11.0软件包统计分析各位点的基因型分布和等位基因频率.结果:COX-2-8473位点多态性的各基因型频率在病例组及对照组中分布均无显著差异(P>0.05),但COX-2-1195位点多态性的基因型频率在二组中分布有显著性差异(P<0.001),结果显示CRC患者COX-2-1195AG基因型在病例组的频率较对照组显著增高(校正后OR=2.23;95%CI:1.50-3.32),AA基因型在病例组中的频率亦较对照组高(校正后OR=2.46;95%CI:1.51-4.02),A等位基因携带者在病例组中的频率高于对照组(校正后OR=2.27;95%CI:1.55-3.34).各基因型分布在结肠癌及直肠癌中的分布无显著性差异(P>0.05).COX-2-1195A等位基因与淋巴结转移及TNM分期有显著相关性.结论:COX-2-1195位点AG/AA基因型是CRC的风险因素,且与CRC的淋巴结转移及TNM分期相关.