Significance of COX-2 expression in human renal cell carcinoma cell lines

Accumulating evidences indicate that cyclooxygenase (COX)-2 plays an important role in tumorigenesis in many human cancers. Yet the relationship between COX-2 and human renal cell carcinoma (RCC) remains unclear. The aim of our study was to evaluate COX-2 expression in human RCC cell lines and its role in tumorigenesis of human RCC. Among the human RCC cell lines (SMKT-R4, OS-RC-2, ACHN) and normal renal cell line RPTEC, COX-2 overexpression was found in OS-RC-2 cells both at mRNA and protein levels. COX-2 sense- and antisense-orientated vectors were constructed and transferred into RCC cells. Significant suppression of cellular proliferation was demonstrated in OS-RC-2 antisense transfectants, whereas promotion was found in SMKT-R4 sense transfectants by colony-forming assay despite the observation that COX-2 specific inhibitor NS398 exhibited similar IC50 among RCC cell lines by MTT assay. In comparison with parent cells and sense transfectants, significant suppression of COX-2 expression and PGE2 production and increase in butyrate-induced apoptosis were observed in OS-RC-2 antisense transfectants by Western blot, ELISA assay and FACS analysis, respectively. Furthermore, tumor growth and angiogenesis of OS-RC-2 antisense transfectants in nude mice was significantly suppressed and the survival time of these mice was significantly prolonged. Our study demonstrates that COX-2 is overexpressed in OS-RC-2 RCC cell line and plays an important role in tumorigenesis of the cells in vivo, which implies that COX-2 may be a therapeutic target for COX-2-expressing RCC, and that suppression of COX-2 expression by antisense-based strategy may have potential utility in treatment of COX-2-expressing RCC.     

老年食管鳞癌组织环氧合酶-2表达与放疗敏感性的关系

目的 食管鳞癌的预后影响因素较多,本研究旨在探讨环氧合酶-2(cyclooxygenase-2,COX-2)表达与老年(≥60岁)食管鳞癌的相关性及临床意义.方法 选取2008-03-01-2011-04-30在郑州大学附属肿瘤医院接受根治性放疗的43例老年食管癌患者,均行6MVX射线根治性放疗,照射剂量60 Gy.根据放疗疗效分为放射抗拒组和敏感组.采用免疫组织化学SP法对两组癌组织进行COX-2检测并对照分析.选取20例健康人组织作为对照组,比较老年食管癌患者组与对照组之间COX-2表达水平有无差异,探讨食管鳞癌组织COX-2蛋白表达与临床因素的关系.以3年总生存率为指标,对其性别、临床分期、病理类型、肿瘤部位、COX-2表达水平、化疗等与生存时间的关系进行单因素及多因素分析,探讨COX 2与预后的关系.结果 放疗后3年的总生存率为23.3％(10/43).对照组COX-2均阴性表达,老年(≥60岁)食管癌组全部阳性表达.放疗抗拒组与敏感组食管鳞癌组织中COX 2表达率分别为91.67％(11/12)和29.03％(9/31),抗拒组明显高于敏感组,差异有统计学意义,P＜0.001.COX-2的表达水平与食管癌的临床分期相关(P=0.003),与性别、病理类型和肿瘤位置等因素无关,P＞0.05.COX 2蛋白表达单因素分析显示,临床分期和COX-2表达水平与患者的预后有关,P＜0.01.多因素分析显示,临床分期和COX-2表达水平是患者预后不良的独立因素,P＜0.01.结论 COX-2的表达与食管癌的临床分期相关.COX-2的表达水平可作为老年食管鳞癌放射敏感性和预测放疗近期疗效的重要指标,临床分期和COX-2表达水平可能是影响长期生存的一个独立预后因素.     

食管鳞状细胞癌中Survivin和COX-2的表达与临床病理因素的关系

目的：探讨凋亡抑制蛋白Survivin和COX-2在食管鳞状细胞癌中的表达及相关性。方法：应用免疫组织化学SP法检测Survivin和COX-2蛋白在51例食管鳞状细胞癌和30例切缘正常食管粘膜中的表达,分析Survivin和COX-2表达与食管鳞状细胞癌临床病理因素的关系及两者的相关性。结果：食管鳞状细胞癌组织和切缘正常食管粘膜中,Survivin蛋白阳性率分别为74.51%和6.67%;COX-2蛋白阳性率分别为56.86%和16.67%。统计学分析结果表明,Survivin和COX-2在食管鳞状细胞癌的表达均高于切缘正常食管粘膜（Р〈0.01）。Survivin蛋白在食管鳞状细胞癌中的表达阳性率与性别、年龄、肿瘤大小、TNM分期、淋巴结转移等因素无关（Р〉0.05）,但与肿瘤分化程度相关（Р〈0.05）。COX-2蛋白在食管鳞状细胞癌的表达阳性率性别、年龄、肿瘤大小、肿瘤分化程度、TNM分期、淋巴结转移等因素均无关（Р〉0.05）。51例食管鳞状细胞癌组织中Survivin与COX-2之间具有显著正相关性（Р〈0.01）。结论：Survivin与COX-2蛋白在食管鳞状细胞癌中均过表达,可能是食管鳞状细胞癌发生的早期事件。并且两者表达具有相关性,提示Survivin与COX-2可能存在一个共同的分子通路,并在食管鳞状细胞癌发生、发展中增强各自的作用。在食管鳞状细胞癌中两者关系的分子基础值得进一步研究。     

食管鳞癌COX-2蛋白表达意义研究进展

与对食管腺癌的作用相似,环氧合酶-2(COX-2)的表达也可能影响食管鳞癌的发生、发展及预后.多数食管鳞癌有COX-2蛋白不同程度的表达,但其真正临床意义尚未明了.COX-2选择性抑制剂可抑制食管鳞癌细胞生长,诱导细胞凋亡,可能对化疗和放疗起增敏作用.     

COX-2和VEGF在食管鳞癌中的表达及其临床病理意义

目的研究COX-2和VEGF在食管鳞癌中的表达及临床病理意义。方法应用免疫组化方法检测45例食管鳞癌和20例正常食管粘膜组织中COX-2、VEGF和CD34蛋白的表达。结果食管鳞癌中COX-2和VEGF的表达较正常食管组织明显增加。COX-2和VEGF阳性表达与肿瘤组织浸润深度、淋巴结转移及分期有关(P<0.05)。COX-2和VEGF的表达与MVD均相关。COX-2与VEGF的表达具有相关性。结论COX-2和VEGF在食管鳞癌中高表达,参与了食管癌的发生、浸润及转移,可以作为判断食管鳞癌生物学行为的指标之一。COX-2和VEGF在促进肿瘤血管生成调节机制中可能存在着协同效应关系。     

Dual inhibition of 5-LOX and COX-2 suppresses esophageal squamous cell carcinoma

COX-2 and 5-LOX are up-regulated in ESCC. This study aims to determine the efficacy of COX-2 inhibitor, 5-LOX inhibitor and their combination on ESCC. Nimesulide can suppress cell growth and promote apoptosis, accompanied with a decrease of PGE(2) production. AA861 has the similar effect with a down-regulation of LTB(4). In animal experiment, the tumor volumes in drug-treated groups were significantly smaller with the lowest rates of Ki-67 positive cells. In conclusion, either COX-2 inhibitor or 5-LOX inhibitor can suppress ESCC. Dual inhibition of COX-2 and 5-LOX pathway may present a superior anticancer efficacy to either inhibition of COX-2 or 5-LOX alone.     

磷酸化小窝蛋白-1在食管鳞癌中的表达及意义

目的:检测磷酸化小窝蛋白-1（PY14caveolin-1,PY14cav-1）在不同食管组织中的表达,探讨PY14cav-1与食管癌发生、发展的关系。方法:收集60例食管鳞状细胞癌患者手术标本,采用免疫组织化学方法分析和检测PY14cav-1在食管癌组织、癌旁组织及正常食管组织中的表达情况,分析PY14cav-1表达水平与食管癌发生、发展的关系。结果:PY14cav-1在食管鳞癌组织中的表达水平明显高于癌旁组织与食管正常组织中的表达水平,差异具有统计学意义(P<0.05)。PY14cav-1与食管癌的临床分期呈正相关性,随着肿瘤临床分期的升高表达增强,差异具有统计学意义(P<0.05)。淋巴结转移组中PY14cav-1的表达明显高于无淋巴结转移组,差异具有统计学意义(P<0.05)。PY14cav-1的表达与肿瘤的分化程度呈负相关性（P=0.034）。结论:PY14cav-1的表达与食管癌分化程度、临床分期和淋巴结转移有关,可能参与了食管癌的侵袭和转移,在食管癌的发生和发展过程中起着重要的作用,很可能成为潜在的治疗靶点及判断食管癌预后有价值的肿瘤标记物。     

ⅠB～ⅡA期子宫颈鳞状细胞癌组织中环氧合酶-2表达与预后的关系

 目的　探讨ⅠB～ⅡA期子宫颈鳞状细胞癌组织中环氧合酶-2（COX-2）表达及其与预后的关系。方法　采用免疫组织化学EnVision法检测107份子宫颈癌组织和30份正常子宫颈组织中COX-2的表达水平。结果　早期子宫颈鳞状细胞癌组织COX-2阳性表达率为55.14 ％，明显高于正常子宫颈组织（0）（χ2 = 56.916，P＜0.01）。单因素分析显示子宫颈癌组织COX-2的表达水平与临床分期、子宫颈深间质浸润和脉管内瘤栓有关（P＜0.05）；与淋巴结转移、年龄、复发或转移、肿瘤大小及病理分化程度无关（P＞0.05）。COX-2阳性组和COX-2阴性组的总体生存曲线差异无统计学意义（χ2 = 0.103，P＞0.05）。结论　早期子宫颈鳞状细胞癌组织COX-2的阳性表达与临床分期、子宫颈间质浸润深度和有无脉管内瘤栓有关，但与预后无关，COX-2表达在早期子宫颈鳞状细胞癌患者预后中的意义尚有待验证。     

COX-2和MMP-2在宫颈鳞癌组织中的表达及临床意义

目的:探讨环氧合酶-2(COX-2)和基质金属蛋白酶-2(MMP-2)在宫颈鳞癌组织中的表达、相互关系及临床意义.方法: 38例宫颈鳞状细胞癌为实验组,慢性宫颈炎及正常宫颈组织各10例为对照组.采用免疫组化SP法分别检测COX-2和MMP-2在各组中的表达情况.结果: COX-2和MMP-2在正常、炎性、鳞癌组织中均有表达,但鳞癌中的表达显著高于对照组(P＜0.05);正常及宫颈炎组之间无显著性差异(P＞0.05);COX-2和MMP-2的表达与宫颈癌的临床分期、病理分级、淋巴转移无明显相关性(P＞0.05);但在有淋巴转移组和无淋巴转移组中表达强弱不同.在宫颈鳞癌组织中MMP-2、COX-2 蛋白的表达之间存在显著正相关(r=0.581,P＜0.01).结论: COX-2和MMP-2与宫颈鳞癌的发生、发展相关,并在其侵袭、转移中可能发挥了作用,且两者关系密切.     

Clinicopathological significance of human macrophage metalloelastase expression in esophageal squamous cell carcinoma

OBJECTIVE: Human macrophage metalloelastase is referred to as matrix metalloproteinase (MMP-12), its function in tumors is contradictory. The current study was undertaken to investigate the role of MMP-12 in esophageal squamous cell carcinoma (SCC). PATIENTS AND METHODS: We analyzed the levels of MMP-12 mRNA expression in 67 patients with primary esophageal SCC by Northern blot analysis and the tissues were subjected to in situ hybridization analysis for MMP-12. Immunohistochemical staining was performed to detect the macrophages infiltrated in esophageal SCCs. RESULTS: MMP-12 mRNA was detected in 27 of 67 esophageal SCC samples by Northern blot analysis. In situ hybridization and immunohistochemical staining revealed that MMP-12 mRNA signals are located mainly in tumor cells. The frequency of lymph node metastasis was significantly higher in the MMP-12-positive (MMP-12(+)) subgroup than MMP-12-negative (MMP-12(-)) subgroup (p < 0.05); furthermore, invasion was significantly deeper in the MMP- 12(+) subgroup than in the MMP-12(-) subgroup (p < 0.01). MMP-12 mRNA was inversely correlated with prognosis (p < 0.05). However, Cox multivariate analysis revealed that upregulation of MMP-12 was not related to prognosis. CONCLUSIONS: MMP-12 gene expression was associated with the progression of esophageal SCC; however, it was not an independent prognostic factor.     

环氧合酶-2和血管内皮生长因子在食管癌中的表达及临床意义

目的探讨食管癌组织中环氧合酶乞（COX-2）和血管内皮生长因子（VEGF）的表达及临床意义。方法采用SP免疫组化法检测60例食管癌患者组织和20例正常食管黏膜标本中COX-2和VEGF蛋白的表达。结果60例食管癌组织中,COX-2阳性表达率为68．3％,VEGF为76．7％;均明显高于正常食管黏膜,差异有统计学意义（P〈0．05）。COX-2和VEGF在食管癌组织中的表达呈显著正相关（rs=0．526,P〈0．0001）。VEGF表达与食管癌区域淋巴结转移密切相关,COX-2和VEGF表达与食管癌的临床分期、组织分化程度、浸润深度等无明显相关性（P〉0．05）。结论COX-2蛋白和VEGF蛋白在食管鳞癌中均呈高表达,二者的表达呈显著正相关。VEGF与食管癌区域淋巴结转移有相关性。     

Thymidine phosphorylase in human esophageal squamous cell carcinoma

BACKGROUND: Experimental evidence has shown that thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and has angiogenic activity. The enzymatic activity of dThdPase was needed for the angiogenesis by the enzyme. These observations were catalysts for the current study. METHODS: The authors examined retrospectively the expression of the angiogenic factor dThdPase in 163 primary esophageal squamous cell carcinomas and its association with angiogenesis and clinicopathologic findings. To determine whether dThdPase expression was a prognostic factor after adjustment for the established prognostic factors and microvessel count, the authors conducted a survival analysis using the Cox proportional hazards model. RESULTS: dThdPase was expressed significantly more frequently (P < 0.001) in esophageal carcinomas (83 of 163, 50.9%) than in adjacent nonneoplastic esophageal tissue samples (20 of 163, 12.3%). Microvessel counts were significantly higher (P < 0.001) in dThdPase positive carcinomas (18.3+/-6.2) than in dThdPase negative carcinomas (8.2+/-7.5). Significant correlations were observed between dThdPase expression and numerous clinicopathologic findings, including pT, pN, pM categories; lymphatic invasion; venous invasion; and residual tumors. Prognostic variables studied using a Cox hazard regression model confirmed that dThdPase expression was an independent prognostic factor in esophageal squamous cell carcinoma, although pN category was the best predictor of patient survival. CONCLUSIONS: This study indicated that in esophageal squamous cell carcinoma, dThdPase expression is associated with angiogenesis and is an unfavorable prognostic factor. These findings implied that the inhibition of dThdPase would improve the prognoses of some patients with dThdPase positive esophageal tumors.     

Dysregulated expression of HOX and ParaHOX genes in human esophageal squamous cell carcinoma

Homeobox genes function as master regulators in embryonic morphogenesis. We hypothesized that homeobox genes are essential to maintain tissue- or organ-specificity even in adult body and that the dysregulated expression of homeobox genes results in tumor development and progression. To better understand the roles of homeobox genes in development and progression of esophageal cancer, we analyzed the expression patterns of 39 HOX genes and 4 ParaHOX (CDX1, CDX2, CDX4 and PDX1) genes in esophageal squamous cell carcinoma (ESCC) and normal esophageal mucosa tissues. A total of 48 primary ESCC tissues and 7 normal esophageal mucosa tissues were resected from patients who underwent radical surgery without any preoperative chemotherapy or radiotherapy. The expression of HOX and ParaHOX genes were analyzed by a quantitative real-time RT-PCR method and immunohistochemistry. The expression levels of 24 HOX genes, CDX1, CDX2 and PDX1 were significantly higher in ESCC compared to normal mucosa (p<0.01, Mann-Whitney U test). The Immunohistochemical study revealed that HOXA5 and D9 proteins were more cytoplasmic in ESCC than normal mucosa cells. Our data indicate that the disordered expression of HOX and ParaHOX genes are involved in the development of ESCC or its malignancy.     

c-erbB-2 oncoprotein expression related to chemoradioresistance in esophageal squamous cell carcinoma

PURPOSE: Esophageal carcinoma is a challenging target for radiotherapy. To improve treatment efficacy, an investigation of a predictive factor is desirable. In this study, we evaluated the significance of apoptosis and immunohistochemical staining for p53, Ki-67, c-erbB-2 (HER-2/neu), Ku (p70/p80), and DNA-PKcs for predictive markers of the responsiveness to chemoradiotherapy in esophageal squamous cell carcinoma. MATERIALS AND METHODS: This retrospective analysis consisted of 34 patients with esophageal squamous cell carcinoma in whom tumor biopsy was performed before treatment. They were divided into chemoradiosensitive (n = 13) and chemoradioresistant (n = 21) groups according to the tumor response evaluated at a total radiation dose of 40 Gy. The biopsy samples were examined with immunohistochemical staining for various factors and with an in situ nick end labeling method for apoptosis. The examined data were compared between the two groups. RESULTS: The difference in the Ki-67, p53, Ku (p70/p80), DNA-PKcs labeling indexes and the apoptosis index in tumor cells between the chemoradiosensitive and chemoradioresistant groups was not statistically significant. The expression of c-erbB-2 oncoprotein was statistically significant in the chemoradioresistant group (p = 0.02), although it did not correlate with survival. CONCLUSIONS: c-erbB-2 immunostaining is useful for the prediction of chemoradioresistance in esophageal squamous cell carcinoma.     

Role of human papillomaviruses in esophageal squamous cell carcinoma

Esophageal cancer (EC) is responsible for almost half a million deaths worldwide annually and has a multifactorial etiology, which may account for its geographical variation in incidence. In the last 30 years the potential of human papillomaviruses (HPV) as oncogenes or co‐factors in the tumorigenic process of esophageal squamous cell carcinoma (ESCC) has been widely studied. While the etiology of HPV in cervical and certain other anogenital and aerodigestive cancers has been established, results regarding its role in EC have been largely inconclusive. A causal association can be evaluated only with a case‐control study, where normal controls are compared to ESCC cases for the presence of HPV. We reviewed all studies investigating ESCC tissue for HPV DNA and identified 139 that met our inclusion criteria, of which only 22 were case‐control studies. Our results support previous findings of higher levels of HPV detection in high‐risk ESCC regions than in areas of low risk. In addition, we confirm that the role of HPV in ESCC remains unclear, despite an accumulation of studies on the subject. The variations in investigative technique, study design and sample types tested may account for the lack of consistency in results. There is a need for a meta‐analysis of all case‐control studies to date, and for large, well‐designed case‐control studies with adequate power to investigate the association. The potential benefits of prophylactic HPV vaccines could be evaluated if HPV is identified as an etiological factor in EC, highlighting the need for further research in this area.     

Serial analysis of gene expression of esophageal squamous cell carcinoma: ADAMTS16 is upregulated in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. To identify potential diagnostic markers for ESCC and therapeutic targets for ESCC, we used Serial Analysis of Gene Expression (SAGE) on one ESCC sample. We obtained a total of 14 430 tags, including 5765 that were unique. By comparing SAGE tags from the ESCC sample with those from normal human squamous esophagus, we found several genes that were differentially expressed between ESCC and normal squamous esophagus. Among these, we focused on the ADAM metallopeptidase with thrombospondin type 1 motif, 16 (ADAMTS16) gene because quantitative RT‐PCR analysis showed a high level of ADAMTS16 expression in eight out of 20 ESCC samples (40%), but not in 15 kinds of normal tissues. Western blot analysis also showed upregulation of ADAMTS16 protein in ESCC tissues. Furthermore, ADAMTS16 protein was detected in culture media from the TE5 esophageal cancer cell line. Knockdown of ADAMTS16 in TE5 cells inhibited both cell growth and invasion ability. Our present SAGE data provide a list of genes potentially associated with ESCC. ADAMTS16 could be a novel diagnostic and therapeutic target for ESCC. (Cancer Sci 2010; 101: 1038–1044)     

IRF2在食管鳞癌中的表达及临床意义

目的:探讨干扰素调节因子2（interferon regulatory factor 2,IRF2）在人食管鳞癌组织中的表达及其与病理特征和预后的关系。方法:采用免疫组化SP法检测69例食管鳞癌组织和45 例癌旁组织的IRF2 表达,分析其与临床病理特征及预后之间的关系。结果:IRF2在食管鳞癌组织中的表达明显高于癌旁组织,并与肿瘤分化程度、淋巴转移及TNM分期明显相关。单因素生存分析发现IRF2表达、分化程度、淋巴转移与患者的无进展生存显著相关,多因素分析则证实IRF2是预后的独立风险因子。结论:IRF2在食管鳞癌中高表达,并且是不良预后的独立风险因子,提示其可能发挥癌基因的功能。