Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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. Frequent allelic losses at this region in various malignancies, including non-small cell lung carcinomas (NSCLCs), imply that FHIT may represent a tumour suppressor gene (TSG). Increasing evidence suggests that multiple TSG impairment has a synergistic effect on tumour growth. The present study of 67 NSCLCs investigated the allelic imbalance (AIm) within the FHIT locus and its relationship with p53 abnormalities, kinetic parameters [proliferative activity or proliferation index (PI) and apoptotic index (AI)], and ploidy status of the carcinomas. Allelic imbalance at FHIT was observed in 35 out of 55 informative (heterozygous: H) cases (64%). Similar frequencies of loss of heterozygosity (LOH) were noticed among squamous cell lung carcinomas and adenocarcinomas. The high percentage of AIm in stage I tumours (71%) is indicative of its relatively early involvement in NSCL carcinogenesis. No association was found between LOH at FHIT, kinetic parameters, and ploidy status of the tumours. Concurrent loss at FHIT and p53 overexpression [FHIT(LOH)/p53(P)] was the most frequent pattern and was observed in 39% of the informative cases. The latter pattern was not associated with smoking, supporting the hypothesis that in patients with a history of tobacco exposure, FHIT allelic loss may not be a consequence of p53 checkpoint defects, but the outcome of tobacco-induced mutagenesis. Statistically significant differences in the presence of FHIT(LOH)/p53(P) and FHIT(LOH)/p53(N) patterns were noted at the proliferative and apoptotic level, whereas ploidy was similar amongst all groups, implying that wild-type (wt) p53 may play a safeguard role against altered FHIT function. However, the possibility of a masking effect from wt p53 cannot be excluded, since the FHIT(LOH)/p53(P) profile demonstrated a higher growth index (GI=PI/AI mean value ratio) than FHIT(H)/p53(P) (32 vs. 8), although this was not significant. Further studies are needed in order to elucidate the role of FHIT and its relationships with other cell-cycle regulatory molecules involved in NSCL carcinogenesis.
 ...
PMID:Association of allelic loss at the FHIT locus and p53 alterations with tumour kinetics and chromosomal instability in non-small cell lung carcinomas (NSCLCs). 1116 16

Investigation on intratumoral genetic heterogeneity provides an important insight into the roles of genetic alterations in human carcinogenesis and clues to clonal origin of tumors. Intratumoral heterogeneity of genetic changes of cervical cancer has not been described so far. In this study, we analyzed the intratumoral heterogeneity of chromosome 3p deletions and X-chromosome inactivation patterns in multiple microdissected samples from each individual cervical cancer, attempting to understand the roles of 3p deletions in development of cervical cancer and its clonal origin. Totally, 120 normal and lesional samples from 14 cases of fresh cervicalcancers were analyzed. Frequency and patterns of allelic losses of 3p were assessed by polymerase chain reaction (PCR) amplification of 12 microsatellite markers flanking the frequently deleted regions of 3p, followed by Genescan analysis in an ABI 377 DNA sequencer. Loss of heterozygosity was recorded as heterogeneous pattern (LOH present in parts of samples or LOH involving different alleles among different samples) and homogeneous pattern (LOH involving identical alleles in all samples from the tumor). Allelic loss affecting at least one marker was detected in 8 of 14 cases (57%). Allelic losses, both homogeneous and heterogeneous, were frequently detected at FHIT gene region (D3S1300, 40% and 60%; D3S4103, 27.3% and 54.6%), 3p21.3-21.2 (D3S1478, 27.3% and 45.5%), and 3p24.2-22 (D3S1283, 30% and 50%). Seven of eight LOH-positive tumors exhibited homogeneous allelic loss involving at least one of these three 3p loci. Allelic losses were present in the CIN lesions synchronous with invasive lesions positive for LOH. Our findings suggest essential roles of genes on these 3p loci, particularly the FHIT gene in participating in clonal selection and early development of cervical cancer. Most interestingly, with the combination of LOH analysis and X-chromosome inactivation analysis, we provided the first clear genetic evidence of polyclonal origin of cervical invasive cancer in two of eight cases. This finding strongly suggests the importance of field defect (possible human papilloma virus) in cervical carcinogenesis.
 ...
PMID:Analysis of intratumoral heterogeneity of chromosome 3p deletions and genetic evidence of polyclonal origin of cervical squamous carcinoma. 1123 6

The deficiencies of nucleotide excision repair (NER) factors are involved in rare genetic diseases such as xeroderma pigmentosum (XP) with increased risk of developing cancer on sun-exposed areas of the skin. However, the abnormality of NER factors in human sporadic carcinoma remains unclear. Loss of heterozygosity (LOH) analysis, using the microdissected tissues, for the XPA, XPB, XPC, XPD, XPE, XPF, XPG and the transcription-coupled repair factor, Cockayne syndrome B (CSB) revealed that NER factors were abnormal in 30.0% (3/10 cases) of oral squamous cell carcinomas. Furthermore, 10.0% of oral carcinomas exhibited LOH for NER factors without LOH for tumor suppressor genes such as p53, FHIT, APC, BRCA1, BRCA2 and DCC. These observations raise the possibility that alterations of NER factors may be involved in carcinogenesis in human oral squamous cell carcinoma.
 ...
PMID:Loss of heterozygosity of nucleotide excision repair factors in sporadic oral squamous cell carcinoma using microdissected tissue. 1149 30

The FHIT gene, encompassing the FRA3B fragile site at chromosome 3p14.2, is a candidate tumor suppressor gene involved in multiple tumors, including esophageal carcinoma. We analyzed Fhit expression using an immunohistochemical method in invasive carcinoma, carcinoma in situ (CIS) and dysplasia, in paraffin sections of 75 esophageal squamous cell carcinomas (ESCs) to further elucidate the role of Fhit protein in esophageal carcinogenesis. In addition, we also examined whether Fhit expression correlated with p53 expression and apoptosis. Compared to adjacent normal mucosa, significant loss or reduction of Fhit expression was noted in 67 of 75 (89.3%) invasive ESCs, in 13 of 19 (68.4%) CIS lesions, and in 10 of 23 (43.5%) dysplastic lesions. There was a progressive loss or reduction of Fhit expression with progressive increases in the severity of histopathological changes (p < 0.001). However, there was no association between Fhit expression and clinicopathological findings, including tumor stage, lymph node metastasis, or overall survival. Moreover, Fhit expression was not significantly associated with p53 expression and apoptosis. These results indicate that abnormal Fhit expression is a common event in the early stage of ESC development and may occur independently of p53 expression and apoptosis mechanisms.
 ...
PMID:Reduced Fhit expression occurs in the early stage of esophageal tumorigenesis: no correlation with p53 expression and apoptosis. 1157 76

The FHIT gene is altered in several types of tumors and abnormal expression of Fhit protein have also been reported in some preneoplastic lesions. We have determined the Fhit expression on histological samples of 26 patients affected by preneoplastic lesions who developed a gastric cancer within 2 years. The expression of the Fhit protein was always present in all preneoplastic lesions, while the Fhit protein immunostaining was distributed unevenly in 10 cases and completely lost in 6. The complete loss of Fhit expression only in areas of neoplastic low differentiation suggests that FHIT gene takes part in late gastric carcinogenesis.
 ...
PMID:Fhit protein expression in human gastric cancer and related precancerous lesions. 1160 39

Alteration of the FHIT gene was investigated in lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl) amine (BHP) in male Wistar rats. Animals at 6 weeks of age were given 2000 p.p.m. of BHP in drinking water for 12 weeks, then maintained without further treatment until killed at the end of week 25. A total of 25 lung adenocarcinomas were obtained and total RNAs were extracted from each for assessment of aberrant transcription of the FHIT gene by reverse transcription (RT)-polymerase chain reaction (PCR) analysis. Aberrant transcripts were detected in 15 adenocarcinomas (60%) as absence in the regions of nucleotides (nt) -9 to 279, -98 to 279, -98 to 348 or -98 to 447. Genomic DNAs were also extracted from all 25 adenocarcinomas and exons 5-9 were examined for mutations, using PCR-single strand conformation polymorphism (SSCP) analysis and sequencing. A mutation was detected in only one adenocarcinoma (4%), an ACC to ATC (Thr to IIe) transition at codon 76. Southern blot analysis of eight tumors did not show any evidence of gross rearrangement or deletion of the FHIT gene. Western blot analysis revealed reduced expression of Fhit protein in six out of 10 adenocarcinomas (60%). These results suggest that alteration of the FHIT gene may be involved in the development of lung adenocarcinomas induced by BHP in rats.
Carcinogenesis 2001 Dec
PMID:FHIT alterations in lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine in rats. 1175 34

The majority of hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in DNA mismatch repair genes, especially in MLH1 and MSH2. Tumours in such patients also show microsatellite instability characteristic for DNA repair defects. The FHIT gene, a candidate tumour suppressor gene located at 3p14.2 has been shown to be involved in carcinogenesis of many human tissues, including digestive tract tissues. In our study, we characterized Fhit protein expression in hereditary and sporadic colorectal cancers (CRC). Our intention was to determine if cancers with mutations in the mismatch repair genes, MSH2 and MLH1, would show more frequent inactivation of the FHIT gene. Sixteen HNPCC and 28 sporadic CRC cases were examined by standard immunohistochemical analyses. Both study groups comprised carefully and selectively chosen cases. We have observed higher frequency of loss or reduction of Fhit protein expression in hereditary CRC than in sporadic cases (44% vs. 25%). Although this difference was not statistically significant (p = 0.17), possibly due to the small number of available tumour specimens, the tendency is interesting. More extensive studies on a larger number of cases should be done in the HNPCC group to confirm statistical significance. Our results suggest that the FHIT gene plays an important role in carcinogenesis of at least one fourth of all colorectal cancers.
 ...
PMID:Fhit protein expression in hereditary and sporadic colorectal cancers. 1176 99

To determine the alterations of the FHIT (fragile histidine triad) gene in oral squamous cell carcinoma (OSCC), this study examined mutation, promoter methylation, mRNA transcription, and protein expression of FHIT in OSCC associated mostly with the use of betel and/or tobacco. Analyses of the coding exons (exons 5-9) identified a deletion of one base in intron 4 in one tumour and a deletion of exon 7 in two tumours. Using bisulphite genomic sequencing, 28% of the informative subjects exhibited promoter methylation. An aberrant FHIT transcript spanning from exon 3 to exon 10, which was verified by RT-PCR analysis, was identified in 36% of the OSCC subjects, 50% of the oral pre-invasive lesions, and 5% of the non-cancerous match tissue. An abnormal immunohistochemical level of Fhit was detected in 41% of OSCC subjects. A statistically significant association was found between aberrant transcription of the FHIT gene and an abnormal level of Fhit immunoreactivity. The results indicated that alteration of FHIT is a frequent occurrence in OSCC and thus suggests that the aberrance in FHIT transcription could be an early event of oral carcinogenesis.
 ...
PMID:Multiple molecular alterations of FHIT in betel-associated oral carcinoma. 1185 93

FHIT (Fragile Histidine Triad) is a human tumor suppressor gene. The Fhit protein is believed to inhibit tumor growth by inducing apoptosis through interaction with diadenosine triphosphate (Ap(3)A). The latter is first sequestered and eventually hydrolyzed by Fhit to ADP and AMP. Thus, the balance between the cellular Ap(3)A level and Fhit enzymatic activity may affect cell death or survival. Increasing the Ap(3)A level, e.g., by inhibition of the enzyme, should prevent apoptosis and thus sustain tumorigenesis. To test if certain carcinogenic transition metals could inhibit the enzymatic activity of Fhit, purified human Fhit protein [30 nM in 1.25 mM poly(vinylpyrrolidone)], expressed in and isolated from E. coli, was incubated at pH 6.8 (50 mM HEPES buffer in 150 mM NaCl) with 120 microM Ap(3)A in the presence of 5 mM Mg(II) (activating cation) and 0-100 microM Ni(II), Cu(II), Zn(II), Cd(II), Co(II), Cr(III), As(III), or As(V). The reaction mixtures were analyzed by HPLC. The results revealed a strong inhibitory potential of Cu(II) [0.4], followed by Ni(II) [3.5] >or= Zn(II) [7.0] >> Cr(III) [73] > Cd(II) [98] >> Co(II) [432] [the numbers in brackets are IC(50) values, microM]. As(III) and As(V) had no effect. As revealed by spectrophotometry, mass spectrometry, and gel electrophoresis, the exceptionally strong inhibition by Cu(II) was associated with Fhit dimerization through formation of a disulfide bond. The other metals and also H(2)O(2) and NO did not cause the dimerization. Thus, the effect of Cu(II) must be due to its reaction with Cys-39 bearing the only thiol group in Fhit monomer. Since Cys-39 is not readily accessible in the Fhit molecule, the reaction is most likely facilitated by conformational changes which follow the coordination of Cu(II) by the surface histidines 35, 94, and/or 96. The observed inhibition of Fhit may be mechanistically involved in metal-mediated toxicity and carcinogenesis.
 ...
PMID:In vitro inhibition of the enzymatic activity of tumor suppressor FHIT gene product by carcinogenic transition metals. 1189 78

The genes specifically involved in endometrial cancers have not yet been discovered. The FHIT gene, a tumour suppressor located at 3p14.2, is altered in many human tumours, including those derived from the female genital tract. We have thus investigated the status of Fhit protein expression in endometrial carcinomas (EC), and its association with histological grade of malignancy in order to determine if Fhit expression is inactivated in EC and if so, whether it is inactivated during initiation or progression. Recent studies have reported that alteration in the FHIT locus detected by DNA and RNA analysis is well correlated with loss of Fhit protein expression in tumours. Thus, we characterised Fhit protein expression as an indication of FHIT gene status in 35 cases of EC of different histological grade (G1: 13 cases; G2: 14 cases; G3: 8 cases). In our group of cancers, Fhit protein expression was absent or reduced in 37% (13/35) of EC. The first 13 cases, judged as G1, showed Fhit deficiency in approximately 38.5% of cases (5/13). For G2 and G3 tumours these numbers were similar and accounted for approximately 35.7% (5/14) and approximately 37.5% (3/8), respectively. No statistical difference was found for Fhit expression among the various groups of tumours, which allowed us to conclude that morphological grade does not seem to be an important factor. Our results suggest that Fhit inactivation is an early event in carcinogenesis of the endometrium. As this observation is contrary to some already published reports, another independent study with larger amounts of material is necessary to determine this issue definitely.
 ...
PMID:Fhit protein expression in endometrial cancers: no correlation with histological grade. 1191 81


<< Previous 1 2 3 4 5 6 7 8 9 Next >>