胃癌脆性组氨酸三体FHIT蛋白表达的研究

脆性组氨酸三联体 ( Fragile histidine triad, FHIT) 基因最近在国外成功分离并定位于染色体 3p14.2. FHIT基因不仅横跨家族性肾细胞癌的易位断点 t(3 ∶ 8)(p14.2;q24), 同时也见于大多数人类的共同脆性位点 FRA3B[1]. 研究发现 FHIT基因结构异常及表达缺失见于多种类型的肿瘤细胞株和原发癌组织 , 包括肺癌、乳腺癌、头颈部癌、食道癌、胃癌、胰腺癌、肾癌和宫颈癌等 [2～ 4], 这说明它可能是多种肿瘤的抑制基因 , 在人类恶性肿瘤的发生中 , 其作用可能不亚于 p53[5].     

脆性组氨酸三联体基因及其表达蛋白在肺癌发病机制中的研究进展

脆性组氨酸三联体（FHIT）基因是一种重要的抑癌基因,在非小细胞肺癌（NSCLC）早期和癌前病变中常见到其蛋白缺失,反映了FHIT基因改变是肺癌发生的中早期分子事件。在FHIT蛋白的参与下,促进铁氧化还原蛋白的电子传递功能,促进了癌细胞在氧化应激环境中的凋亡,FHIT蛋白再表达与铂剂联合增强了肿瘤细胞对凋亡的应答。FHIT／FRA3B的异常变化出现早、频率高、检测方便,对阐明人种、遗传多态性、地理因素、生活环境、呼吸疾病等在肺癌发病机制中的影响具有重要的意义。     

FHIT基因与胃癌的关系

FHIT基因是定位于染色体3p14．2区域的一个候选抑癌基因,因含脆性位点FRA3B, 该基因具有不稳定性,其异常一般发生在与外界接触的器官上皮肿瘤中。胃癌是与环境致癌物密切相关的肿瘤,因而研究胃癌中FHIT基因的异常,对阐明胃癌的发生发展具有重要的理论基础和临床意义。现综述FHIT基因与胃癌关系的研究进展。     

FHIT基因与胃癌的关系

FHIT基因是定位于染色体3p14．2区域的一个候选抑癌基因,因含脆性位点FRA3B,该基因具有不稳定性,其异常一般发生在与外界接触的器官上皮肿瘤中。胃癌是与环境致癌物密切相关的肿瘤,因而研究胃癌中FHIT基因的异常,对阐明胃癌的发生发展具有重要的理论基础和临床意义。现综述FHIT基因与胃癌关系的研究进展。     

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。     

FHIT基因与泌尿系肿瘤

FHIT基因跨越脆性部位FRA3B和(t3;8)易位断裂处,定位于染色体3P14.2的一个抑癌候选基因。人类多种肿瘤组织或肿瘤来源的细胞系中出现3号染色体短臂高频率杂合性缺失(lossofheterozygosity,LOH)。但其与泌尿系肿瘤的关系尚不清楚。就该基因与泌尿系肿瘤的关系的研究进展进行综述。     

胃癌组织中hMSH2、FHIT蛋白表达与幽门螺杆菌感染关系的研究进展

hMSH2是DNA MMR系统的重要基因,其在肿瘤发生发展中的作用已成为研究的热点.脆性组氨酸三联体(fragile histidine triad,FHIT)是已经确定的新的抑癌基因,因含脆性位点FRA3B,其基因具有不稳定性,与许多恶性肿瘤有密切的关系.本文就错配修复基因hMSH2、FHIT和Hp关系的研究进展进行综述.     

Identification of unstable sequences within the common fragile site at 3p14.2: implications for the mechanism of deletions within fragile histidine triad gene/common fragile site at 3p14.2 in tumors

The FRA3B, at 3p14.2, lies within the fragile histidine triad (FHIT) gene and is the most highly expressed of the common fragile sites observed when DNA replication is perturbed by aphidicolin. Common fragile sites are highly unstable regions of the genome. Large intragenic deletions within FHIT, localized within the FRA3B sequences, have been identified in a variety of tumor cells. To characterize the FRA3B deletions in tumor cells and identify FRA3B sequences that are required for fragile site induction, we used microcell-mediated chromosome transfer to isolate hybrid cell clones that retain chromosome 3 homologues with various deletions within FRA3B. Detailed molecular mapping of the FHIT/FRA3B locus in the resultant hybrid cells revealed a complex pattern of instability within FRA3B. Each tumor cell line contained multiple chromosome 3 homologues with variable deletion patterns, often with discontinuous deletions, suggesting that the process of breakage and repair within FRA3B is an ongoing one. By comparing the approximate location of the breakpoints in the hybrid clones, we identified 11 recurring breakpoint/repair regions within the FRA3B. A comparison of the frequency of breaks/gaps within FRA3B in the hybrid clones with various deletions of FRA3B sequences revealed that the loss of FRA3B sequences does not reduce the overall rate of breakage and instability within the remaining FRA3B sequences. The majority of breaks occurred in the proximal portion of the FRA3B, in a 300-kb interval between exon 4 and the proximal 50 kb of intron 5. Our observations suggest that there is no single sequence within the FRA3B that influences breakage or recombination within this region; however, we cannot rule out the presence of multiple "hot spots" within the FHIT/FRA3B locus. Together, the results suggest that factors other than the DNA sequence per se are responsible for the formation of DNA breaks/gaps.     

Common chromosomal fragile sites and cancer: focus on FRA16D

A growing body of experimental evidence supports the view that certain human chromosomal fragile sites have roles to play in cancer. The principle lines of evidence are at the level of mutation mechanism and gene function. Most research in this area has previously focussed on the FRA3B common fragile site and the FHIT gene that spans this site. Here we review recent progress in characterising the second most readily observed common fragile site, FRA16D, and the WWOX gene that spans it. Comparative analyses of FRA3B/FHIT and FRA16D/WWOX reveal some striking similarities suggesting that these sites and their associated genes may play a part in a normal protective response of cells to environmental stress.     

Alteration of the fragile histidine triad gene early in carcinogenesis: an update

An association between common chromosome fragile sites and frequent chromosomal deletions in cancer has been observed and led to the hypothesis that genes at fragile sites may play a role in tumor development. In 1996, the human fragile histidine triad gene, FHIT, was identified by positional cloning at 3p14.2, a chromosomal region spanning the carcinogen-sensitive, common fragile site FRA3B. FHIT gene is lost and inactivated in a large fraction of tumors and early in carcinogenesis. A group of ancestral cancerous cells that carry FHIT alterations, expanding in succeeding cell generations, exhibits a hallmark in carcinogenesis scenario.     

Evidence that instability within the FRA3B region extends four megabases

FRA3B is the most frequently expressed common fragile site localized within human chromosomal band 3p14.2, which is frequently deleted in many different cancers, including cervical cancer. Previous reports indicate aphidicolin-induced FRA3B instability occurs over approximately 500 kb which is spanned by the 1.5 Mb fragile histidine triad (FHIT) gene. Recently an HPV16 cervical tumor integration, 2 Mb centromeric to the published FRA3B region, has been identified. FISH-based analysis with a BAC spanning the integration has demonstrated this integration occurs within the FRA3B region of instability. These data suggest that the unstable FRA3B region is much larger than previously reported. FISH-based analysis of aphidicolin-induced metaphase chromosomes allowed for a complete characterization of instability associated with FRA3B. This analysis indicates that fragility extends for 4 Mb. Within this region are a total of five genes, including FHIT. FRA3B gene expression analysis on a panel of cervical tumor-derived cell lines revealed that three of the five genes within FRA3B were aberrantly regulated. A similar analysis of genes outside of FRA3B indicated that the surrounding genes were not aberrantly expressed. These data provide additional support that regions of instability associated with CFSs and the genes contained within them, may play an important role in cancer development.     

Down-regulation of fragile histidine triad expression in prostate carcinoma

BACKGROUND: The fragile histidine triad (FHIT) gene is a tumor suppressor gene that belongs to the histidine triad family of nucleoside binding proteins. The gene encompasses the common human chromosomal fragile site, the FRA3B locus at chromosome 3p14.2, and is expressed in most normal adult tissues and tumor cell lines. Numerous studies have indicated that the FHIT gene on chromosome 3p may play an important role in human neoplasia, although very few studies have investigated the FHIT gene in prostate carcinoma. METHODS: Using immunohistochemical analyses, the authors studied the expression of FHIT in prostate tumors from 84 radical prostatectomy specimens to determine whether there were any correlations between FHIT expression and various clinicopathologic characteristics. RESULTS: The percentages of cells stained with antibody to FHIT were significantly lower overall for tumor cells compared with normal cells (P = 0.0001). FHIT immunostaining intensity also was significantly lower for tumor cells compared with normal cells (P = 0.0001). A weak but statistically significant correlation (P = 0.045) was demonstrated with the presence of extraprostatic extension in the patient samples. No other significant correlation was seen between the percentage of cells stained for FHIT or FHIT immunostaining intensity and Gleason grade, tumor stage, tumor size, lymph node metastasis, surgical margins, vascular invasion, perineural invasion, or the presence of high-grade prostatic intraepithelial neoplasia. CONCLUSIONS: The data presented indicate a down-regulation of the FHIT tumor suppressor gene in prostate carcinoma and, thus, propose a potential target for therapeutic intervention.