FHIT基因及其与食管癌关系的研究进展

脆性组氨酸三联体（FHIT）基因是一个候选抑癌基因,其抑癌作用可能通过诱导凋亡而实现。在多种肿瘤特别是环境致癌物引起的肿瘤中常有FHIT基因的异常改变。FHIT基因可能通过调控细胞周期,诱导细胞凋亡发挥抑制肿瘤的作用,其失活机制主要表现为启动子区域CPG岛甲基化、缺失及异常转录。此文拟就FHIT基因与食管癌的发生、发展、治疗及预后等几方面进行综述。     

FHIT基因与子宫颈癌的相关性研究

脆性组氨酸三联体(FHIT)基因是近年来发现的定位于人3号染色体短臂(3p14.2)上的候选抑癌基因.许多研究表明其表达改变与人类多种肿瘤关系密切.FHIT基因可能通过调控细胞周期,诱导细胞凋亡发挥抑制肿瘤的作用,其失活机制主要表现为启动子区域CPG岛甲基化、缺失及异常转录.本文重点综述FHIT基因的生物学特性及在宫颈癌发生发展中的作用.     

FHIT基因与子宫颈癌的相关性研究

脆性组氨酸三联体（FHIT）基因是近年来发现的定位于人3号染色体短臂（3p14．2）上的候选抑癌基因。许多研究表明其表达改变与人类多种肿瘤关系密切。FHIT基因可能通过调控细胞周期，诱导细胞凋亡发挥抑制肿瘤的作用，其失活机制主要表现为启动子区域CPG岛甲基化、缺失及异常转录。本文重点综述FHIT基因的生物学特性及在宫颈癌发生发展中的作用。     

FHIT基因与肿瘤

脆性组氨酸三联体(FHIT)基因是一种定位于人类染色体3p14.2上的抑癌基因,在多种器官中都有表达,其包含的脆性位点FRA3B,是基因组中最脆弱的部分.FHIT可促进细胞凋亡,抑制细胞增殖和细胞癌变.FHIT基因高度甲基化、基因缺失、FRA3B脆性位点的改变以及蛋白合成过程中的异常,可导致FHIT基因功能缺失,促进多种肿瘤的发生与发展.将野生型FHIT导入FHIT表达降低或表达缺失的肿瘤细胞中可促进肿瘤细胞凋亡.FHIT基因与其他基因联合治疗可能为肿瘤的治疗提供新的方向.     

FHIT基因与食管癌发生发展相关性的研究

脆性组氨酸三联体(fragilehistidinetriad,FHIT)基因是1996年克隆确定的一个人类基因,它是作为一个候选抑癌基因被提出的,它被发现在多种肿瘤组织中表达异常。属于组氨酸三联体基因家族,定位于染色体3p14.2区域,其cDNA长1095bp。经研究发现FHIT基因的主要作用为:1)FHIT可诱导细胞凋亡。2)FHIT蛋白可能通过泛素结合酶来调控细胞周期。食管癌是人类常见肿瘤,我国是食管癌高发国家,所以研究其早期诊断方法有很大的临床价值,近年来在研究食管癌的发生与FHIT基因的关系时发现:食管癌在早期阶段大都有FHIT基因的表达缺失。而FHIT基因的甲基化是其中的重要机制,其甲基化是FHIT基因失活的前提。同时,研究发现监测FHIT基因表达缺失对与食管癌的早期诊断及估计预后有一定价值。     

FHIT基因与食管癌发生发展相关性的研究

脆性组氨酸三联体（fragilehistidinetriad，FHIT）基因是1996年克隆确定的一个人类基因，它是作为一个候选抑癌基因被提出的，它被发现在多种肿瘤组织中表达异常。属于组氨酸三联体基因家族，定位于染色体3p14．2区域，其cDNA长1095bp。经研究发现FHIT基因的主要作用为：1）FHIT可诱导细胞凋亡。2）FHIT蛋白可能通过泛素结合酶来调控细胞周期。食管癌是人类常见肿瘤，我国是食管癌高发国家，所以研究其早期诊断方法有很大的临床价值，近年来在研究食管癌的发生与FHIT基因的关系时发现：食管癌在早期阶段大都有FHIT基因的表达缺失。而FHIT基因的甲基化是其中的重要机制，其甲基化是FHIT基因失活的前提。同时，研究发现监测FHIT基因表达缺失对与食管癌的早期诊断及估计预后有一定价值。     

FHIT基因与皮肤癌

FHIT基因是组氨酸三联体基因家族的成员,在嘌呤代谢中参与编码一个AP3A水解酶。该基因在3号染色体上包含常见的脆性部位FRA3B,并且致癌物质引起的损伤可以导致染色体易位从而致使基因的转录本异常。事实上,这种基因的异常转录本在所有的食管、胃和结肠癌中发现大约有一半出现异常。研究显示FHIT基因可能通过调控细胞周期,诱导细胞凋亡发挥抑制肿瘤的作用。其失活机制主要表现为启动子区域CPG岛甲基化、缺失及异常转录。同时有研究表明FHIT基因与皮肤癌的发生、发展、转移和预后有着密切的关系。本文就FHIT基因与皮肤癌关系研究最新进展做出综述。     

FHIT基因与皮肤癌

FHIT基因是组氨酸三联体基因家族的成员,在嘌呤代谢中参与编码一个AP3A水解酶。该基因在3号染色体上包含常见的脆性部位FRA3B,并且致癌物质引起的损伤可以导致染色体易位从而致使基因的转录本异常。事实上,这种基因的异常转录本在所有的食管、胃和结肠癌中发现大约有一半出现异常。研究显示FHIT基因可能通过调控细胞周期,诱导细胞凋亡发挥抑制肿瘤的作用。其失活机制主要表现为启动子区域CPG岛甲基化、缺失及异常转录。同时有研究表明FHIT基因与皮肤癌的发生、发展、转移和预后有着密切的关系。本文就FHIT基因与皮肤癌关系研究最新进展做出综述。     

支气管上皮癌前病变FHIT基因稳定性及其蛋白表达

FHIT基因位于3p14.2,为肿瘤候选抑制基因.FHIT异常表达广泛存在于肺、食管、胃、乳腺及肾脏等恶性肿瘤组织.实验表明FHIT参与细胞凋亡,FHIT与p53的联合基因治疗,启动两条或更多的凋亡途径,可抑制肿瘤生长[1].近来FHIT基因在肺癌前病变发生中的作用引起了特别的关注,因此我们对支气管上皮癌前病变FHIT基因稳定性及其蛋白表达进行检测,为FHIT基因应用于肺癌前病变的早期诊断及预防治疗提供实验依据.     

外源性FHIT基因对人乳腺癌MDA-MB-436细胞恶性表型的影响

目的:研究外源性脆性组氨酸三联体(FHIT)基因的表达对乳腺癌MDA-MB-436细胞增殖的影响并探讨其机制.方法:通过脂质体将外源性FHIT基因的真核表达质粒PEGFP-FHIT和空载体分别转染FHIT表达缺失的乳腺癌细胞MDA-MB-436.MTT法分析细胞增殖,流式细胞术观察细胞的凋亡,蛋白质印迹法检测外源性FHIT基因及凋亡相关基因Caspase-3、-8、-9的蛋白表达.结果:PEGFP-FHIT组细胞的生长抑制率和凋亡率明显高于空载体组和对照组,PEGFP-FHIT组细胞Caspase-3、-9活性片段表达上调.结论:外源性FHIT基因表达能抑制MDA-MB-436细胞增殖,其机制可能是通过激活Caspase途径从而诱导细胞凋亡.     

Fragile histidine triad expression delays tumor development and induces apoptosis in human pancreatic cancer.

The fragile histidine triad (FHIT) gene is a tumor suppressor gene that is altered by deletion in a large fraction of human tumors, including pancreatic cancer. To evaluate the potential of FHIT gene therapy, we developed recombinant adenoviral and adenoassociated viral (AAV) FHIT vectors and tested these vectors in vitro and in vivo for activity against human pancreatic cancer cells. Our data show that viral FHIT gene delivery results in apoptosis by activation of the caspase pathway. Furthermore, Fhit overexpression enhances the susceptibility of pancreatic cancer cells to exogenous inducers of apoptosis. In vivo results show that FHIT gene transfer delays tumor growth and prolongs survival in a murine model mimicking human disease.     

Clinicopathological significance of the fragile histidine triad transcription protein expression in laryngeal carcinogenesis

The fragile histidine triad (FHIT), frequently lost in many cancers, was identified as a candidate tumor suppressor gene at chromosome 3p locus 14.2. Loss of the FHIT protein because of the alteration or loss of heterozygosity by genetic deletion occurs in a variety of epithelial tumors including head and neck cancer. However, the biological function of the FHIT protein is still unknown and its role in intrinsic cellular proliferation remains particularly controversial in preinvasive lesions and invasive tumors of the head and neck. To clarify the role of the FHIT protein in laryngeal squamous cell carcinoma (LSCC) and to examine whether the expression of FHIT could be a prognostic parameter for laryngeal carcinogenesis, we investigated the relationship between the expression of the FHIT protein, other tumor suppressor gene products (p53 and p16), the cellular proliferation marker (Ki-67) and the survival time of patients with LSCC. In our study, there were significant differences (p<0.05) in the expression of FHIT between low grade dysplasia and LSCC. Additionally, survival time analysis showed a significant correlation between the reduction of FHIT expression and the length of disease-free survival (p<0.05) in patients with T1-T2 N0 laryngeal carcinoma. However, we did not confirm a relationship between the expression of FHIT, the other tumor suppressor gene products (p53 and p16) or the cellular proliferation marker (Ki-67). In conclusion, we provided evidence that the reduction of FHIT levels may be a useful prognostic indicator for the clinical outcome of laryngeal SCC. Our findings indicated that FHIT utilizes a pathway independent of p53 and is involved in abnormal cell proliferation via the breakdown of G0-G1 arrest in the larynx and apoptosis during multistep carcinogenesis of the larynx.     

Restoration of fragile histidine triad (FHIT) expression induces apoptosis and suppresses tumorigenicity in breast cancer cell lines

The fragile histidine triad (FHIT) gene at chromosome 3p14.2 is a tumor suppressor gene that is altered mainly by deletion in a large fraction of human tumors, including breast cancers. To evaluate the potential of FHIT gene therapy in this type of cancer, we have studied the biological effects of adenoviral FHIT transduction (Ad-FHIT) in breast cancer cell lines. The results showed that, after FHIT restoration in BT-549, MDA-MB-436, and HCC1806 cells, they underwent apoptosis by activation of the intrinsic pathway. In all three cell lines infected with Ad-FHIT, we have found activation of caspase-2, which is required for permeabilization of mitochondria, release of cytochrome c, and apoptosis. Furthermore, Fhit overexpression produces alteration in cell cycling properties, as well as reduction of the tumorigenic potential in nude mice.     

Induction of apoptosis and inhibition of tumorigenicity and tumor growth by adenovirus vector-mediated fragile histidine triad (FHIT) gene overexpression.

We studied the effects of fragile histidine triad (FHIT) gene overexpression mediated by an adenoviral vector, Ad-FHIT, on cell proliferation, apoptosis, and cell cycle kinetics in human cancer cells and on tumorigenicity and tumor growth in nude mice. Overexpression of the FHIT gene significantly inhibited cell growth in various Ad-FHIT-transduced human lung cancer cells and head and neck carcinoma cells with FHIT gene abnormalities, but not in normal human bronchial epithelial cells. Fewer than 20% of cells in all Ad-FHIT-transduced cells survived at 7 days after transduction. Overexpression of the FHIT gene induced cell apoptosis and altered cell cycle processes. The apoptotic cell population markedly increased, and cells accumulated in S phase after Ad-FHIT transduction. The tumorigenicity of human H1299 lung cancer cells transduced by Ad-FHIT, in comparison with that of the control transductants and untreated cells, was eliminated in vivo. Subcutaneous tumor growth in nude mice who received intratumoral injections of Ad-FHIT, at a total dose of 3 x 10(10) plaque-forming units/tumor for H1299 tumors and 4 x 10(10)/tumor for A549 tumors, were suppressed by more than 85% and 90%, respectively, compared with that in nude mice who received injections of empty vector at the same dose or with PBS alone. Together, our results suggest that the FHIT gene, when delivered at high efficiency by a recombinant adenoviral vector, functions as a tumor suppressor gene both in vitro and in vivo.     

Prevalence of fragile histidine triad expression in tumors from saudi arabia: a tissue microarray analysis.

AIM: The fragile histidine triad (FHIT) gene was discovered and proposed as a tumor suppressor gene for most human cancers. It encodes the most active common human chromosomal fragile region, FRA3B. We studied the prevalence of loss of FHIT expression in various tumors and correlated its loss with various clinicopathologic features. METHODS: To determine whether the absence of FHIT expression correlates with clinical variables such as grade, stage, and survival time, we assessed FHIT expression using immunohistochemistry. More than 1,800 tumors from more than 75 tumor categories were analyzed by immunohistochemistry in a tissue microarray format. RESULTS: Loss of FHIT expression ranged from 19% in ovarian tumors to 67% in lung cancers. Clinical and pathologic features like grade, stage, tumor size, and lymph node metastasis showed correlation with loss of FHIT expression in some tumors. No difference was seen in the survival patterns and loss of FHIT expression in any of the tumor groups studied. CONCLUSIONS: Loss of FHIT expression is an ubiquitous event in the multistep, multifactorial carcinogenesis process. FHIT may be altered at different stages in different types of cancers. Most of the tumors with a wider prevalence of loss of FHIT expression as an early event show a correlation with clinicopathologic features. However, in some of the tumors, FHIT expression is lost as a late event and is only seen in a fraction of the tumors.     

Abnormal transcripts of FHIT gene in Chinese brain tumors

FHIT located at chromosome 3p14.2 was discovered and proposed as a candidate tumor suppressor gene in several cancers. To determine whether the FHIT gene at 3p14.2 is altered in Chinese brain tumors, we examined 13 brain tumors for deletions within FHIT locus. Evaluation of the FHIT gene in the panel of brain tumors led to a comprehensive mutation analysis. The complete sequence of the FHIT gene was determined and deletions between exon 5-8 were found in all 13 cases. In addition, single point mutation of amino acid from two glioblastoma and one atypical meningioma cases and multiple amino acid mutations from one pituitary tumor were observed. Our results support the hypothesis that FHIT gene alteration is involved in tumorigenic development of human neoplasms.     

FHIT基因与喉癌相关性的研究

目的 研究ＦＨＩＴ基因在喉癌发生中的作用。方法 应用ＲＴ－ＰＣＲ技术筛查了喉细胞系Ｈｅｐ－２，宫颈癌细胞系ＨｅＬａ和２０例原发性喉癌的ＦＨＩＴ基因转录本，对其中的２例异常转录本进行了测序分析。同时，对另外６０例原发性喉癌ＦＨＩＴ基因进行了微卫星多态分析。结果 在２０例喉癌中，１４例，显示ＦＨＩＴ基因异常转录本，Ｈｅｐ－２和ＨｅＬａ细胞系ＦＨＴ基因转录本均存在缺失。