Disease relevance of FHIT

• F&D adenomas showed significantly stronger fragile histidine triad (FHIT) expression and lower p53 reactivity than similarly sized polypoid adenomas, whereas proliferative and apoptotic indices were similar in both groups [1].
• FHIT gene transfer into lung cancer cell line H460 lacking Fhit protein expression resulted in reversion of tumorigenicity [2].
• Clear cell-type renal cell carcinomas (clear RCC) are characterized almost universally by loss of heterozygosity on chromosome 3p, which usually involves any combination of three regions: 3p25-p26 (harboring the VHL gene), 3p12-p14.2 (containing the FHIT gene), and 3p21-p22, implying inactivation of the resident tumor-suppressor genes (TSGs) [3].
• FHIT inactivation is particularly important in squamous cell carcinomas that are often associated with precursor dysplastic lesions [4].
• Allelic deletion of FHIT was related to tumor histology with 4 of 20 adenocarcinomas (20%) displaying loss of heterozygosity (LOH) compared with 12 of 22 (55%) nonadenocarcinomas (P = 0.03) [5].

High impact information on FHIT

• Fragile-HIT proteins (FHIT) cleave diadenosine tetraphosphate, which is potentially produced during activation of the SSBR complex [6].
• The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers [7].
• Aberrant transcripts of the FHIT locus were found in approximately 50% of esophageal, stomach, and colon carcinomas [7].
• The FHIT gene 3p14.2 is abnormal in lung cancer [8].
• Abnormal lung tumor transcripts lack two or more exons of the FHIT gene [8].

Chemical compound and disease context of FHIT

• FHIT expression was determined by immunohistochemistry in formalin-fixed paraffin-embedded tissues from 54 squamous cell carcinomas (SCC) and 44 adenocarcinomas (AC) of the lung [9].
• MATERIALS AND METHODS: We examined the expression of Fhit protein in 50 endometrial carcinomas and 19 normal endometrial tissues by immunohistochemistry, and this expression was correlated with clinicopathological parameters, p53 expression, sex steroid receptor status and abnormal FHIT transcripts [10].
• In this report, we describe an improved extruded DOTAP:cholesterol (DOTAP:Chol) cationic liposome that efficiently delivers therapeutic tumor suppressor genes p53 and FHIT, which are frequently altered in lung cancer, to localized human primary lung cancers and to experimental disseminated metastases [11].
• LOH at FHIT is associated with estrogen- and progesterone-negative breast tumors, high S-phase fraction, reduced patient survival, and LOH at chromosome regions 6q, 7q, 8p, 9p, 11p, 11q, 13q, 16q, 17p, 17q, 18q, and 20q [12].
• Increased Sensitivity to Cisplatin in Non-Small Cell Lung Cancer Cell Lines after FHIT Gene Transfer [13].

Biological context of FHIT

• The tumor-suppressor gene FHIT is involved in the regulation of apoptosis and in cell cycle control [2].
• A significant inhibition of cell growth was observed in H460/FHIT cells [2].
• One putative target, 3p14.2, contains the common fragile site, FRA3B, a hereditary renal carcinoma-associated 3;8 translocation and the candidate tumor suppressor gene, FHIT [14].
• The smallest deletion (CC19) was shown not to involve FHIT coding exons and no DNA sequence alterations were present in the transcript [14].
• Chromosome 3p14 alterations in lung cancer: evidence that FHIT exon deletion is a target of tobacco carcinogens and asbestos [15].

Anatomical context of FHIT

• The FHIT gene product is highly expressed in the cytoplasm of renal tubular epithelium and is down-regulated in kidney cancers [16].
• In addition, transcripts from TSG101, FHIT and seven other genes were analysed in RNA isolated from normal peripheral blood lymphocytes [17].
• Furthermore, loss of FHIT expression is also seen in metastatic axillary lymph node [18].
• FHIT and TSG101 in thyroid tumours: aberrant transcripts reflect rare abnormal RNA processing events of uncertain pathogenetic or clinical significance [19].
• Alterations of FHIT gene and P16 gene in nickel transformed human bronchial epithelial cells [20].

Associations of FHIT with chemical compounds

• The FHIT gene, located at the FRA3B fragile site of chromosome 3p14.2, encodes a 16.8 kD homologue of the yeast enzyme diadenosine tetraphosphate (Ap(4)A) hydrolase [21].
• MEASUREMENTS: Single stage and nested reverse transcription polymerase chain reaction (RT-PCR) products of FHIT, TSG101, and TP53 were analysed by agarose or polyacrylamide gel electrophoresis and sequenced [19].
• OBJECTIVE: To study the alterations of FHIT gene and P16 gene in malignant transformed human bronchial epithelial cells induced by crystalline nickel sulfide using an immortal human bronchial epithelial cell line, and to explore the molecular mechanism of nickel carcinogenesis [20].
• Exon amplification from cosmids covering this deleted region allowed identification of the human FHIT gene, a member of ther histidine triad gene family, which encodes a protein with 69% similarity to an S. pombe enzyme, diadenosine 5', 5''' P1, P4-tetraphosphate asymmetrical hydrolase [7].
• Histidine triad nucleotide-binding protein (HINT), a dimeric purine nucleotide-binding protein from rabbit heart, is a member of the HIT (histidine triad) superfamily which includes HINT homologues and FHIT (HIT protein encoded at the chromosome 3 fragile site) homologues [22].

Physical interactions of FHIT

• Chromatin immunoprecipitation detected exogenous E2F-1 binding to the recognition site in FHIT 5' region [23].

Regulatory relationships of FHIT

• Ubc9-induced inhibition of diadenosine triphosphate hydrolase activity of the putative tumor suppressor protein Fhit [24].
• Our results therefore reveal a novel molecular mechanism consisting of FHIT-mediated tumor suppression and the interaction of FHIT with other cellular components in the pathways regulating p53 activity [25].
• The results suggest that the DNA lesions related to the expression of FRA3B induce the long-patch repair and that the low DNA polymerase alpha activity and inefficient repair process during G2 phase is involved in the expression of FRA3B [26].

Other interactions of FHIT

• Our findings suggest that hypermethylation of the RAR-beta and FHIT may play an important role in the early stage of esophageal squamous cell carcinogenesis [27].
• Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer [28].
• None of the other nine candidate genes were methylated in seminomas, but MGMT (44%), APC (29%) and FHIT (29%) were frequently methylated in NSTGCTs [29].
• Cell lines included those from patients with germline BRCA1 and FHIT gene mutations and others with possible genetic predisposition [30].
• We have found that in addition to FHIT, expression of the LTF gene from CER1 at 3p21.33-p21.31 was lost in all 9 tumours analyzed [31].

Analytical, diagnostic and therapeutic context of FHIT

• Samples were reanalyzed for exon loss using PCR; 13 of 30 tumors failed to generate a PCR product, and 20 of 30 tumors were missing at least one FHIT exon or had loss (loss of heterozygosity or deletion) of one microsatellite marker, suggesting that regions of the gene are homozygously deleted [15].
• Moreover, Western blots revealed that the levels of FHIT prior to and following fragile site induction was unchanged, whereas p53 was found at elevated levels after induction [32].
• Loss of FHIT expression was associated with a higher proliferation index (ki-67, P=0.007; flow cytometry, P<0.004) and lower apoptotic index (P=0.018) [9].
• Aberrant transcripts of FHIT and TSG101 using nested RT-PCR were reported in many human tumours [33].
• Genomic DNA was also analysed by polymerase chain reaction and sequencing (FHIT) or by Southern blotting (TSG101) [19].

References