Abnormal Fhit expression is an independent poor prognostic factor for cervical cancer

We analysed the expression of the fragile histidine triad (FHIT) gene in cervical cancer to evaluate its clinical relevance in relation to human papillomavirus (HPV) infection. A total of 73 women with cervical cancer of stage Ib or more advanced (67 squamous cell carcionomas, four adenocarcinomas, two adenosquamous carcinomas) were examined for Fhit expression by immunohistochemistry. They were further analysed for the presence of HPV and its subtype. Abnormal expression of Fhit (absent or reduced Fhit expression) was observed in 52 cases (71.2%). The high-risk HPV DNAs for cervical cancer, including type 16, 18, 31, 33, 51, 52, 58, 68, were identified in 63 cases (86%). The abnormal Fhit expression was not related to the clinicopathological factors including histology, tumour stage, and HPV type. Notably, the 5-year survival of patients showing the abnormal Fhit expression was significantly poorer than those showing normal Fhit expression (64 versus 87%, P=0.035). Interestingly, the mean age of the patients with the abnormal Fhit expression was significantly less than those with the normal Fhit expression (51.6 versus 58.7 years of age, P=0.027, student's t-test). These data imply that the aberrant Fhit expression could be a poor prognostic factor independent of HPV. In the light of a high incidence of abnormal Fhit expression in younger patients and HPV as a key player in cervical carcinogenesis, abnormal Fhit expression may accelerate carcinogenesis in concert with HPV.     

胃癌FHIT基因异常及与EB病毒感染相关性的研究

目的:检测胃癌FHIT基因转录、Fhit蛋白表达以及EB病毒(EBV)的感染情况,探讨EBV感染对FHIT基因异常表达的影响及其与胃癌发生的关系.方法:应用巢式RT-PCR法检测30例胃癌组织和30例配对正常胃黏膜组织中FHIT基因的表达,并对异常转录本进行测序;Western杂交法检测10例胃癌Fhit蛋白的表达;PCR法检测50例胃癌(包括RT-PCR检测30例)EBV的感染情况.结果:正常胃黏膜组织中均检测到正常大小转录本,11例(36.7%)胃癌检测到异常转录本;测序结果1例异常转录本缺失FHIT外显子5～7,1例缺失FHIT外显子4～7;4例(40.0%)Fhit蛋白表达缺失或降低;5例(10.0%)EBV阳性,其中4例(80.0%)同时存在FHIT基因的异常转录本.结论:FHIT基因及其产物Fhit蛋白的缺失在胃癌的发生发展中起重要的作用.EBV感染可能通过引起FHIT基因的异常导致胃黏膜上皮细胞癌变.     

Concordant loss of fragile gene expression early in breast cancer development

The FHIT and WWOX genes encompass the FRA3B and FRA16D fragile sites at chromosomes 3p14.2 and 16q23.3, respectively. Reduced Fhit and Wwox expression has been reported in approximately two-thirds of invasive breast tumors. Expression of these fragile gene products, as well as ErbB2 and p53, were evaluated immunohistochemically in 44 pure and 31 adjacent-to-invasive ductal carcinoma in-situ (DCIS) cases. Reduced Fhit and Wwox expression were observed in (i) 70% and 68% of pure DCIS; (ii) 52% and 55% of DCIS adjacent-to-invasive tumor cases; and (iii) 20% and 50% of adjacent normal tissue in pure DCIS cases. Reduced Wwox expression in adjacent normal tissue was observed in 30% of cases in the DCIS adjacent-to-invasive group. Reduced Fhit and Wwox expression was observed in 61% of adjoining invasive tumors. In all normal, pure DCIS, and DCIS adjacent-to-invasive lesions, Fhit and Wwox expression was positively associated (P = 0.034, P = 0.042, P = 0.004, respectively) and in the invasive component there was a positive trend toward association (P = 0.075). Fhit and Wwox were more frequently reduced in high-grade lesions in the DCIS adjacent-to-invasive (P = 0.025, P = 0.004, respectively). In the pure DCIS group, there was a statistically significant negative association between Fhit and ErbB2 expression in DCIS (P = 0.035). In summary, reduced Fhit and Wwox expression in in-situ breast cancer was associated, which may contribute to the high-grade DCIS-invasive tumor pathway.     

乳腺癌组织FHIT基因位点杂合性缺失及其蛋白表达的研究

目的：探讨FHIT基因与乳腺癌发生发展的关系。方法：运用PCR—变性聚丙烯酰胺凝胶电泳—银染法对FHIT基因住点上5个微卫星位点进行LOH的检测。同时采用免疫组织化学方法检测了40例肿瘤组织中Fhit蛋白的表达情况。结果：37．5％的原发性乳腺癌存在LOH，45％的肿瘤样本发生Fhit表达的缺失或明显下降，两者之间无显著性差异(P=0．000)。结论：FHIT基因位点的LOH及Fhit蛋白表达的缺失及下降是乳腺癌早期的和频发的事件，FHIT基因在乳腺癌的发生发展中起重要的作用。     

Livin和Fhit在乳腺癌中的表达及其临床意义

目的：探讨livin、fhit在乳腺癌中的表达及其临床意义,并分析两者的相关性。方法：用RT-PCR法检测54例乳腺癌组织中livinmRNA、fhitmRNA的表达,并分析其与临床病理因素的关系。结果：livinmR-NA、fhitmRNA在乳腺癌组织中的阳性率分别为63.7%、63.3%。两者阳性表达与患者年龄、激素受体状态无明显相关性（P〉0.05）,livinmRNA阳性表达与临床分期、淋巴结有无转移学有关（P〈0.05）,fhitmRNA阳性表达与肿瘤大小、组织学分级、淋巴结转移有关（P〈0.05）,livinmRNA、fhitmRNA表达呈负相关（r=-0.346,P〈0.001）。结论：乳腺癌中存在livin及fhit的过表达,livin可能通过PI3K/Akt途径下调fhit,成为其促进乳腺癌浸润、转移的可能途径之一。     

Fhit和CerbB-2在乳腺癌进展过程中的表达和意义

脆性组氨酸三联体基因（fragile histidine triad gene,Fhit基因）是1996年Ohta等用定位克隆及外显子捕获技术在3p14-2首先克隆出来的,在多种肿瘤中,均有改变,以缺失为主。目前认为,Fhit基因是一个候选的抑癌基因。CerbB-2已证实是一个与肿瘤侵袭行为相关的癌基因,     

Fhit、Caspase-8基因在膀胱肿瘤组织中的表达及其意义

目的探讨Fhit、Caspase-8基因在膀胱肿瘤组织中的表达及其意义。方法应用免疫组化Elivision法检测Fhit、Caspase-8基因在正常膀胱组织、腺性膀胱炎、膀胱癌旁组织、膀胱癌组织中的表达;用图像分析系统测量Fhit、Caspase-8的平均光密度值。结果Fhit、Caspase-8在正常膀胱组织、腺性膀胱炎、膀胱癌旁组织、膀胱移行细胞癌、膀胱腺癌中的平均光密度值分别为:0.270±0.042、0.248±0.044;0.142±0.040、0.150±0.051;0.240±0.061、0.234±0.053;0.097±0.053、0.108±0.053;0.089±0.026、0.105±0.062。膀胱癌中Fhit、Caspase-8的表达明显低于正常膀胱组(P<0.01),Fhit、Caspase-8在膀胱移行细胞癌中的表达随病理分级上升而减弱(P<0.01),且与分级呈负相关(r分别为-0.700、-0.674,P均<0.01);但与病理分期无关(r=0.456,P=0.025;r=0.337,P=0.107)。Fhit、Caspase-8在膀胱组织中的表达呈正相关(r=0.726,P<0.01)。结论膀胱癌中Fhit表达减弱或缺失伴随着Caspase-8表达的下调,提示膀胱癌的演进过程与Fhit、Caspase-8有密切关系。     

Expression of Fhit, cell adhesion molecules and matrix metalloproteinases in atypical adenomatous hyperplasia and pulmonary adenocarcinoma

Invasive parenchymal-type lung adenocarcinoma develops from atypical adenomatous hyperplasia (AAH), through an intermediate in situ stage of bronchioloalveolar carcinoma (BAC). We examined the expression of the putative tumour suppressor gene product Fhit, cell adhesion molecules CD44v6, E-cadherin and beta-catenin, and matrix metalloproteinase 2 and its inhibitor, TIMP-2, in a range of AAH lesions, BACs and invasive adenocarcinomas, to determine the changes in molecular expression associated with this form of neoplastic progression. Sections of formalin-fixed wax-embedded archival tissue were stained by standard Immunohistochemical techniques and scored semi-quantitatively, resulting in a grading of negative/low- or high-level staining. Fhit protein was retained at high levels in over 90% of AAH and 83% of BAC, but was found in only 6% of stromally invasive tumours (p < 0.0001). CD44v6 staining was high-level in 64% of AAH but fell to 26% in stromally invasive tumour (p = 0.007). E-cadherin and beta-catenin showed the opposite, with more high-level staining as adenocarcinoma developed (p < 0.001). High-level MMP-2 and TIMP-2 expression was relatively infrequent in AAH (32% and 40% respectively), rose in BAC (89% each) but fell in stromally invasive tumour (31% and 17% respectively) (p < 0.01). Unlike in central bronchial carcinogenesis, loss of Fhit expression is a relatively late event in this putative progression of lung adenocarcinogenesis, and has potential as a surrogate marker of invasion, which could be of value in screening patients for lung cancer. Loss of CD44v6 expression follows the convention of falling adhesion molecule expression as malignancy develops. Increased expression of E-cadherin and beta-catenin may reflect increased cell-cell contact as tissue architecture changes in the transition from AAH to adenocarcinoma. Loss of MMP-2 and TIMP-2 in stromally invasive tumour may reflect a particular role for MMP-2 at the BAC stage, with later down-regulation of this particular enzyme.     

Fhit在非小细胞肺癌中的失表达及其意义

目的：探讨Fhit失表达与非小细胞肺癌临床病理特征的关系。方法：随机收集非小细胞肺癌（含癌旁组织和正常肺组织）标本102例，采用免疫组织化学法检测Fhit的表达并结合肺癌的临床病理特征进行分析。结果：Fhit在非小细胞肺癌组织与癌旁细支气管上皮细胞中定位于细胞质。在102例肺癌组织中有31例（30.4%)Fhit免疫组化染色阳性，而在相邻的正常肺组织中100％染色阳性。35例细支气管不典型增生区中7例（20％）阳性。而且Fhit失表达与组织类型、分化程度和临床分期及患者的吸烟史有统计学意义（P＜0.05)。结论：Fhit在非小细胞肺癌中及支气管上皮不典型增生区表达下降或无表达，尤其在鳞癌和吸烟病例中阳性率低，因此Fhit失表达可能与肺癌早期发生及环境致癌物致癌过程有关。