碳酸酐酶Ⅸ与乳腺癌

缺氧是肿瘤微环境的代表性特征之一。肿瘤微环境中氧浓度的波动可引起肿瘤细胞的一系列反应,如凋亡途径的失活、存活途径的激活、侵袭性和转移性表型的诱导、糖酵解代谢途径的转变和新生血管的生成等。血供不足的肿瘤细胞在缺氧环境中,被迫采用能量转换效率低下的无氧呼吸模式。为满足能量需求,     

CXCL9和碳酸酐酶Ⅸ在鼻咽癌患者血清中的表达及其临床意义

目的 研究鼻咽癌患者血清趋化因子(CXCL)9和碳酸酐酶Ⅸ(CAⅨ)水平与其临床病理因素的相关性.方法 选择鼻咽癌患者共32例,结果统计过程中因资料遗失脱落2例,实际完成30例;检测鼻咽癌组和对照组血清CX-CL9和CAⅨ水平;分析血清CXCL9和CAⅨ表达水平与患者的性别、年龄、肿瘤大小、TNM分期、病理类型及淋巴结转移等临床病理参数的相关性;所有患者均给予2年定期随访,比较死亡患者与存活患者血清CXCL9和CAⅨ水平.结果 鼻咽癌组较对照组血清CXCL9和CAⅨ水平均明显增高(P＜0.01);血清CXCL9和CAⅨ表达水平与鼻咽癌患者的性别、年龄、大小及病理类型无明显相关性(P＞0.05),而与鼻咽癌患者TNM分期、淋巴结转移呈明显相关(P＜0.叭).随访2年显示:6例死亡,24例存活;死亡患者入院时血清CXCL9和CAⅨ水平均明显高于存活者入院时(P＜0.01).结论 鼻咽癌患者血清CXCL9和CAⅨ的表达水平明显升高,与鼻咽癌的恶性程度呈显著性相关,可能是评估鼻咽癌患者预后的重要指标.     

碳酸酐酶与肿瘤相关性研究进展

目的:总结国内外关于碳酸酐酶(CA)与肿瘤相关性的研究进展.方法:应用PubMed和CNKI期刊全文数据库检索系统,以“碳酸酐酶(CA)和肿瘤”为关键词,检索2001-01-2011-11的相关文献.纳入标准:1)碳酸酐酶的生物活性;2)碳酸酐酶在癌肿瘤中表达;3)碳酸酐酶表达对癌肿瘤的影响;4)碳酸酐酶对癌患者预后等的影响.根据纳入标准符合分析的文献26篇.结果:CA在机体中主要是催化H2O+CO2+H+(←→)H3CO3+这一包含气体和离子的转换平衡.该平衡对酸碱平衡、气体交换、离子转运等生理过程都十分重要.近年来的研究发现,CA在大多数肿瘤中都有表达,在不同肿瘤中表达的CA同工酶不同,对肿瘤发生、发展、侵袭和转移等过程都起到重要的作用.结论:研究碳酸酐酶与肿瘤的关系,在探索肿瘤发病机制和发展基因的靶向化疗提高抗癌效果等方面都有着有重要的理论意义和临床价值.     

碳酸酐酶Ⅸ及在非小细胞肺癌中的研究进展

肿瘤乏氧代谢与肿瘤的侵袭性及预后不良相关,碳酸酐酶Ⅸ(carbonic anhydraseⅨ,CAⅨ)是一个内生性乏氧标志,近年来对CAⅨ的研究发现,CAⅨ的表达与非小细胞肺癌(NSCLC)患者的生存期、肿瘤侵袭性等因素相关,其高表达可以作为预后不良的预测因素。CAⅨ可以作为治疗的靶点,其抑制剂已经被发现具有抗肿瘤作用,但对肺癌的作用尚需进一步研究。该文主要对CAⅨ及其在NSCLC中的研究进展作一综述。     

胸部肿瘤患者肋间肌碳酸酐酶Ⅲ及其mRNA表达的研究

背景与目的：有研究提示肿瘤可以上调其原发灶及转移灶中的碳酸酐酶(carbonic anhydrase,CA)含量,但至目前为止尚不知肿瘤组织是否会影响其他非转移组织中CA的含量。本研究通过测定CAⅢ及其mRNA在胸部良性肿瘤、肺腺癌患者肋间肌中的表达,探讨CAⅢ在这些疾病状态下的表达调控情况。方法：对昆明医科大学第一附属医院胸外科行开胸肿瘤切除术的38例住院患者取肋间肌组织活检,根据术后肿瘤组织病理结果提示纵隔良性肿瘤10例、肺腺癌12例。肺腺癌组患者根据肿瘤转移情况分为淋巴结转移组(6例)和无淋巴结转移组(6例),根据分化程度分为低分化组(3例)、中分化组(6例)及高分化组(3例),此外,16例单纯胸外伤作为对照组。然后,利用ELISA法定量测定患者肋间肌CAⅢ的浓度,利用Real-time PCR法检测患者肋间肌的CAⅢ mRNA表达水平,分析比较各组患者肋间肌中CAⅢ的浓度定量及其mRNA表达水平差异,探讨CAⅢ在肺腺癌等疾病状况下的表达调控情况。结果：CAⅢ的浓度定量结果方面,与其他2组比较,肺腺癌组患者肋间肌CAⅢ的浓度显著升高(P＜0.01),且淋巴结转移组高于无淋巴结转移组(P＜0.05),CAⅢ浓度在低、中、高分化肺腺癌各组患者肋间肌间的表达差异无统计学意义(P均＞0.05)。在CAⅢ mRNA相对表达量方面(2-△△Ct),与其他2组比较,肺腺癌组患者肋间肌CAⅢ mRNA表达水平显著升高(P＜0.01),且淋巴结转移组高于无淋巴结转移组高(P＜0.01),但CAⅢ mRNA水平在低、中、高分化肺腺癌各组患者肋间肌间差异无统计学意义(P均>0.05)。患者CAⅢ的浓度定量及其mRNA表达水平与患者的FEV1/Pred%(第一秒呼气容积占预计值百分比)呈正相关(P<0.05),与患者的年龄、体质量指数、FEV1/FVC%、PaO2、PaCO2无显著相关性(P均>0.05)。在各组患者,其肋间肌CAⅢ mRNA表达水平与CAⅢ浓度定量呈现一致性表现,即mRNA表达水平升高组,其蛋白浓度定量也升高;相反,mRNA表达水平降低组,其蛋白浓度定量也降低。结论：肺腺癌组患者肋间肌的CAⅢ的浓度定量及其mRNA水平表达均较其他2组高。由于肺腺癌肋间肌CAⅢ的mRNA表达水平与CAⅢ的浓度定量呈现一致性表现,其对CAⅢ的调控可能主要在上游DNA转录水平得到实现,使得其肋间肌CAⅢ mRNA转录水平及蛋白表达异常,进而影响其肋间肌功能状态。     

鼻咽癌组织中CAⅨ和APE表达及其临床意义

背景与目的：鼻咽癌治疗首选放射治疗,其疗效与临床分期的早晚明显相关。因此采用新的技术和方法以进一步提高早期诊断率,进而提高疗效一直是鼻咽癌临床研究的重要课题。本研究通过分析碳酸酐酶Ⅸ（CAⅨ）蛋白和无嘌呤/无嘧啶内切核酸酶（apurinic/apyrimidinic endonuclase,APE）表达与鼻咽癌患者临床特征的关系,探讨其在鼻咽癌诊断和治疗中的价值。方法：应用免疫组织化学法检测54例鼻咽癌和20例鼻咽慢性炎性组织中CAⅨ蛋白和APE蛋白的表达,并对10例鼻咽癌患者放疗前和放疗期间组织中CAⅨ蛋白和APE表达水平进行动态检测。结果：鼻咽癌组织中CAⅨ的阳性表达率显著高于鼻咽慢性炎性组织（P〈0.01）;CAⅨ阳性表达与患者的性别、年龄、T分期、有无颈淋巴结转移和临床分期均无相关性（P〉0.05）。鼻咽癌组织中APE的细胞核阳性表达率高于鼻咽慢性炎性组织,其差异具有统计学意义（P〈0.05）;APE阳性表达与患者的性别、年龄、T分期、有无颈淋巴结转移和临床分期均无关（P〉0.05）。放疗后获得肿瘤局部控制的患者,其放疗期间CAⅨ阳性表达率显著低于放疗前（P〈0.05）。鼻咽癌中CAⅨ和APE的阳性表达未见相关性（r=-0.028,P〉0.05）。结论：CAⅨ的高表达和APE细胞核内高表达可能在鼻咽癌的发生、发展中起重要作用。     

血清碳酸酐酶IX检测对肺癌的诊断意义

背景与目的碳酸酐酶IX(carbonic anhydrase IX,CAIX)是一种跨膜蛋白,参与肿瘤细胞的代谢过程。其在少数正常组织中低表达,但在多种恶性肿瘤组织中广泛表达。检测CAIX在肺癌患者血清中的含量,探讨其对肺癌的诊断价值,分析不同病理类型及TNM分期肺癌患者血清CAIX含量是否存在差异。方法选取47例肺癌患者和31例健康体检者为研究对象,用酶联免疫吸附测定(enzyme linked immunosorbent assay,ELISA)法检测其血清CAIX含量,根据病理类型及TNM分期分组,比较各组血清CAIX差异;绘制血清CAIX诊断肺癌的受试者工作特征曲线(receiver operating characteristic curve,ROC)。结果肺癌组较健康对照组血清CAIX含量明显增高(P<0.001);鳞癌和小细胞癌患者血清CAIX含量明显高于腺癌患者。I期+II期与III期+IV期的肺癌患者血清CAIX含量比较,未发现两者间的差异有统计学意义;血清CAIX诊断肺癌的ROC曲线下面积为0.961,当血清中CAIX阈值为115.115 pg/m L时,敏感度和特异度分别为95.7%和90.3%。结论用ELISA法检测患者血清CAIX有助于肺癌诊断,且具有较高的敏感性和特异性。     

MN/CAⅨ基因在宫颈上皮内瘤变及宫颈鳞癌中的表达

目的:探讨MN/CAIX基因在不同等级宫颈病变中的表达情况,其在宫颈病变的病情检测中的价值.方法:以我院妇科2005年6月至2005年10月阴道镜指引下活检确诊的患者86例为研究对象,其中慢性宫颈炎25例,CIN1级21例,CIN2级15例,CIN3级12例,宫颈鳞癌13例:取宫颈脱落细胞提取总RNA,行逆转录--多聚酶链反应(RT-PCR)观察MN/CAIX基因表达情况.结果:不同宫颈病变脱落细胞的MN/CAIX基因表达情况:宫颈炎12%,CIN1级76.19%,CIN2级86.67%,CIN3级91.67%,宫颈鳞癌92.31%,扩增出MN/CAIX cDNA目的片段.CIN及宫颈磷癌患者的MN/CAIX基因表达率明显高于宫颈炎性病变者(P<0.001).结论:MN/CAIX基因在CIN与宫颈癌中高表达,可用以鉴别宫颈瘤性病变及宫颈癌.宫颈脱落细胞MN/CAIX基因检测可以作为CIN病情监测的辅助指标.MN/CAIX基因可能成为一种有潜力的预测宫颈瘤性病变的肿瘤标记物.     

MN/CAⅨ基因在宫颈上皮内瘤变及宫颈鳞癌中的表达

目的:探讨MN/CAⅨ基因在不同等级宫颈病变中的表达情况,其在宫颈病变的病情检测中的价值。方法:以我院妇科2005年6月至2005年10月阴道镜指引下活检确诊的患者86例为研究对象,其中慢性宫颈炎25例,CIN1级21例,CIN2级15例,CIN3级12例,宫颈鳞癌13例:取宫颈脱落细胞提取总RNA,行逆转录—多聚酶链反应(RT-PCR)观察MN/CAⅨ基因表达情况。结果:不同宫颈病变脱落细胞的MN/CAⅨ基因表达情况:宫颈炎12%,CIN1级76.19%,CIN2级86.67%,CIN3级91.67%,宫颈鳞癌92.31%,扩增出MN/CAⅨcDNA目的片段。CIN及宫颈磷癌患者的MN/CAⅨ基因表达率明显高于宫颈炎性病变者(P<0.001)。结论:MN/CAⅨ基因在CIN与宫颈癌中高表达,可用以鉴别宫颈瘤性病变及宫颈癌。宫颈脱落细胞MN/CAⅨ基因检测可以作为CIN病情监测的辅助指标。MN/CAⅨ基因可能成为一种有潜力的预测宫颈瘤性病变的肿瘤标记物。     

恩度联合放射治疗对Lewis肺癌小鼠生长以及碳酸酐酶Ⅸ和乏氧诱导因子表达的影响

目的 研究使用抗血管生成药物联合放射治疗的荷瘤小鼠肿瘤组织中碳酸酐酶Ⅸ(CA Ⅸ)和乏氧诱导因子-1α(HIF-1α)mRNA的表达变化,并对组织基因表达变化的可能机制进行探讨。方法 建立Lewis肺癌模型,将32只成瘤小鼠随机分为对照组(Control组)、恩度组(ES组)、放射治疗组(RT组)和恩度联合放疗组(ES+RT组),从治疗当天开始,隔日测量肿瘤体积,绘制肿瘤生长曲线。治疗结束后剥离瘤体,使用Real-time PCR方法对各处理组肿瘤组织中CA Ⅸ及HIF-1α mRNA的表达情况进行检测。结果 从肿瘤生长曲线可以看出:ES+RT组与其余三组比较差异有统计学意义(P＜0.05),说明联合组抑瘤效果最好。以对照组为参照,ES组、RT组、ES+RT组CA Ⅸ mRNA的扩增倍数均下降,差异均有统计学意义(P＜0.05),ES+RT组下降最明显。以对照组为参照,ES组、RT组、ES+RT组的HIF-1α mRNA扩增倍数均下降,RT组、ES+RT组具有统计学意义(P＜0.05),ES组差异并无统计学意义(P＞0.05)。HIF-1α mRNA与CA Ⅸ mRNA表达呈正相关(r=0.68,P＜0.01)。结论 恩度联合放疗显著抑制Lewis肺癌小鼠肿瘤的生长;同时能够改善肿瘤乏氧状况,抑制HIF-1α和CA Ⅸ mRNA的表达,可能是放疗增敏作用的机制之一。     

Carbonic anhydrase IX (CA IX) mediates tumor cell interactions with microenvironment

Expression of CA IX is normally restricted to the mucosa of alimentary tract, but on the other hand, it takes place in a high percentage of human cancers derived from tissues which are normally CA IX-negative. It is a transmembrane protein with two extracellular domains: carbonic anhydrase (CA) with a high catalytic activity and a proteoglycan-like segment (PG), mediating cell-cell adhesion. Both CA and PG domains interact with the microenvironment and they could play a role in tumorigenesis, but their roles are poorly understood. The present work characterizes some newly recognized properties of the PG. One of them is a prevalently negative charge, caused by a high proportion of dicarboxylic amino acids. This is reflected by easy dissociation of complexes formed by PG either with monoclonal antibody M75 or with the cell surface receptor already at slightly acidic pH. This property might facilitate separation of cells from the primary tumor. Released cells may subsequently attach elsewhere in the organism and eventually start metastatic growth. Another aim of the present study was to identify human tumor cell lines which are expressing the presumed CA IX receptor molecule. The same cell lines were also tested for the presence of CA IX protein; we found that expression of CA IX and of the receptor is independent of each other. In addition, we examined the species specificity of CA IX receptors. The PG domain, which contains the epitope of mAb M75 -PGEEDLP- overlapping with the binding site for putative receptor is relatively conserved in evolution: human and rat CA IX cross-react with M75 antibody on western blots. Consistently with this, human and rat cells can attach to purified human CA IX protein. On the other hand, murine CA IX contains an entirely different equivalent of PG sequence and it does not react with M75 antibody or attach to human CA IX protein. This is suggestive of the co-evolution of CA IX protein together with its receptor.     

Carbonic anhydrase IX in bladder cancer

BACKGROUND:

The objective of this study was to evaluate the role of carbonic anhydrase IX (CAIX) in urothelial carcinoma of the bladder.

METHODS:

A tissue microarray was constructed that contained 724 tissue samples from 340 patients. Immunohistochemical staining was performed using the antibody MN‐75, the percentage of positive cells was evaluated, and their association with tumor (T) classification, grade, and survival was assessed.

RESULTS:

All normal urothelial tissue samples were negative for CAIX expression, whereas 71% of bladder cancers expressed CAIX. CAIX expression was higher in noninvasive (Ta) versus invasive (T1‐T4) tumors (P < .001), in low‐grade versus high‐grade bladder cancer (P < .001), and in metastases versus the corresponding primary tumor (P = .032). For patients with nonmuscle invasive carcinoma who underwent transurethral resection (TUR), higher CAIX expression was associated with poorer recurrence‐free survival (P = .001). In addition, for patients with T1 tumors who underwent TUR, higher CAIX expression conveyed a 6.5‐fold higher risk of progression into muscle‐invasive disease (P = .006). In patients who underwent cystectomy, higher CAIX expression was associated with worse overall survival (P = .003). Multivariate Cox models revealed that CAIX expression was the strongest, independent prognostic factor of recurrence‐free survival (hazard ratio, 2.29; P = .001) and overall survival (hazard ratio, 1.9; P < .001).

CONCLUSIONS:

CAIX was expressed differentially in noninvasive versus invasive tumors, in low‐grade versus high‐grade bladder cancer, and in primary tumors versus metastases. The current results indicated that CAIX is a strong predictor of recurrence, progression, and overall survival of patients with bladder cancer; and the integration of CAIX expression into conventional prognostic models significantly improved their predictive accuracy. The data suggest a tripartite role of CAIX as a diagnostic, prognostic, and therapeutic molecular marker in bladder cancer. Cancer 2009. © 2009 American Cancer Society.     

Carbonic anhydrase IX in oligodendroglial brain tumors

Background  

Carbonic anhydrase IX is a hypoxia-induced enzyme that has many biologically important functions, including its role in cell adhesion and invasion.     

碳酸酐酶9及其在肾细胞癌防治中作用的研究进展

碳酸酐酶9（carbonic anhydrase IX，CA IX）是新发现的碳酸酐酶家族异构体之一，是由酸性氨基酸组成的跨膜糖蛋白，在调控细胞增殖、转化方面有重要作用。它能催化CO2水解为碳酸和水，参与机体的酸碱平衡，调节细胞内外pH值，有利于肿瘤的生长和转移。CA IX位于VHL肿瘤抑制基因的下游，由HIF-1途径激活，在正常组织中表达极低，在肾细胞癌中高度表达，是其特异性抗原。CA IX的表达水平可预测肾癌患者对白介素-2治疗的反应和生存期，CA IX低表达是不良预后因素。近年来对CA IX相应抗体的研究取得了很大进展，^131I标记的MAbG250在肾癌组织中具有高摄取率和高蓄积率，可对肾癌进行放射性核素显像，用来诊断肾癌；^131I标记的cG250MAb用于治疗晚期肾癌，已显示其安全性和有效性。肾细胞癌CA IX的高度特异性表达使其成为肿瘤疫苗潜在的靶抗原和肾癌治疗的重要靶位，在肾癌靶向治疗方面的应用前景广阔。     

Carbonic anhydrase IX expression is associated with tumor progression and a poor prognosis of lung adenocarcinoma

Carbonic anhydrase (CA) IX catalyzes the hydration of carbon dioxide into carbonic acid and participates in a variety of physiological and biological processes. The aim of this study was to evaluate the prognostic significance of CA IX expression in patients with lung adenocarcinoma. Standard immunohistochemical techniques were used to study CA IX expression in 134 patients who underwent curative resection for adenocarcinoma of the lung at our hospital between January 1995 and December 1996. We evaluated the correlations between CA IX expression levels on cancer cells and clinicopathological factors. CA IX expression was not observed in normal lung tissue or specimens from non-invasive adenocarcinomas. CA IX immunostaining was detected in 33 (24.6%) invasive adenocarcinoma cases. Poor differentiated histological phenotype (p=0.0015), pathological stage (p=0.0400), vascular invasion (p=0.0009) and lymphatic permeation (p=0.0050) were significantly related to CA IX expression. On univariate analysis, CA IX positive cases showed significantly shorter overall survival (p=0.0083) and disease-free survival (p=0.0122). In particular, the overall and disease-free survivals in stages I+II were significantly shorter in the CA IX positive than in the CA IX negative cases (p=0.0269 and 0.0011, respectively). Our results suggest that CA IX expression is strongly associated with tumor progression and indicates a poor prognosis for patients with stages I+II lung adenocarcinoma.     

Carbonic anhydrase IX in early-stage non-small cell lung cancer.

PURPOSE: Tumor hypoxia is associated with poor prognosis and increased tumor aggressiveness. Carbonic anhydrase (CA) IX, an endogenous marker for tumor hypoxia, catalyzes the hydration of carbon dioxide into carbonic acid and contributes to the pH regulation of tumor cells. Therefore, CA IX might allow tumors to acclimate to a hypoxic microenvironment, promoting tumor cell proliferation. We hypothesized that CA IX expression is related to tumor cell proliferation and poor disease-free survival in patients with early-stage non-small-cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: CA IX expression was measured in 75 resected NSCLC tumors to assess prognostic implications for disease-free survival. The relationship of CA IX expression with microvessel density (MVD) and proliferation (Ki-67) index was assessed via colocalization analysis. RESULTS: All patients had operable NSCLC (stage I, 58; stage II, 17). CA IX expression was present in 54 (72%) of 75 patients and was associated with tumor necrosis (P < 0.05). CA IX-positive tumor areas showed greater cell proliferation as measured by Ki-67 index (P < 0.05) and less MVD (P < 0.05) than did CA IX-negative areas in colocalization analysis. The percentage of CA IX-positive tumor cells was significantly related to postoperative recurrence and poor disease-free survival (P < 0.05). Ki-67 index and pathologic stage were also independent prognostic factors for worse disease-free survival (P < 0.05). CONCLUSIONS: CA IX expression of tumor cells may be an indicator for poor disease-free survival in early-stage NSCLC.     

Carbonic anhydrase IX expression and outcome after radiotherapy for muscle-invasive bladder cancer

AimsCarbonic anhydrase IX (CA IX) expression has been described as an endogenous marker of hypoxia in solid neoplasms. Furthermore, CA IX expression has been associated with an aggressive phenotype and resistance to radiotherapy. We assessed the prognostic significance of CA IX expression in patients with muscle-invasive bladder cancer treated with radiotherapy.Materials and methodsA standard immunohistochemistry technique was used to show CA IX expression in 110 muscle-invasive bladder tumours treated with radiotherapy. Clinicopathological data were obtained from medical case notes.ResultsCA IX immunostaining was detected in 89 (∼81%) patients. Staining was predominantly membranous, with areas of concurrent cytoplasmic and nuclear staining and was abundant in luminal and perinecrotic areas. No significant correlation was shown between the overall CA IX status and the initial response to radiotherapy, 5-year bladder cancer-specific survival or the time to local recurrence.ConclusionsThe distribution of CA IX expression in paraffin-embedded tissue sections seen in this series is consistent with previous studies in bladder cancer, but does not provide significant prognostic information with respect to the response to radiotherapy at 3 months and disease-specific survival after radical radiotherapy.     

Carbonic anhydrase IX is highly expressed in hereditary nonpolyposis colorectal cancer.

Carbonic anhydrase (CA) II, CA IX, and CA XII are expressed in various neoplasias and have been linked to tumorigenesis. We examined their expression in three different groups of colorectal cancer [i.e., microsatellite stable (MSS), microsatellite instable (MSI), and hereditary nonpolyposis colorectal cancer (HNPCC)]. First, we analyzed gene expression profiles of 113 specimens by a microarray method to study the expression of various CA isozymes in the subgroups of colorectal cancer. The results indicated that mRNAs for CA II and CA XII are down-regulated and CA IX mRNA is up-regulated in all three tumor categories when compared with the normal tissue. The up-regulation of CA IX was greatest in the HNPCC group. For more information, 77 specimens were immunohistochemically stained to study the levels of CA II, CA IX, and CA XII. Immunohistochemical analyses further confirmed that the subgroups express CA II, CA IX, and CA XII differentially, and the HNPCC tumors express high levels of CA IX. Expression of these CAs did not correlate to Dukes stage or grade of differentiation. Our results show that CAs are differentially expressed in the subgroups of colorectal cancer, and CA IX expression seems to be very high in most cases of HNPCC. CA IX could be a potential diagnostic and therapeutic target in HNPCC.