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

It has been suggested that pulmonary tuberculosis (PT) is associated with lung carcinogenesis. To identify the genetic characteristics of precancerous PT lesions in lung, 20 patients were selected with a 1-month to 36-year history of PT and 20 lung cancer patients with a 2- to 53-year history of previous PT that had undergone lung resection at the Nanfang Hospital from 1999 to 2003; PCR-based microsatellite analysis with DNA extracted from microdissected tissues and immunohistochemical analysis of FHIT protein expression in samples of hyperplasia and cancer obtained from 40 patients were performed. Three microsatellite markers of the FHIT gene for loss of heterozygosity (LOH) analysis were used. LOH of the FHIT locus was frequently found among the lesions of hyperplasia and atypical hyperplasia obtained from 6 patients with a 1- to 36-year history of PT (12 of 30 informative lesions, 40%); none of 70 hyperplastic lesions obtained from 14 patients with a 1- to 11-month history of PT showed LOH at the FHIT gene; 17 of 20 (85%) cancer lesions obtained from 20 lung cancer patients with a 2- to 53-year history of previous PT showed LOH at the FHIT gene, which was significantly higher than hyperplasia and atypical hyperplasia obtained from patients with a 1- to 36-year history of PT in FHIT LOH (Fisher's exact test p = 0.003). Additionally, the level of FHIT protein expression was frequently reduced in the hyperplastic lung epithelial cells of PT with a 1- to 36-year history and cancer tissue. Our findings suggest that allelic loss of the FHIT gene may be involved in carcinogenesis in the lung of patients with PT.
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PMID:Aberrations in the fragile histidine triad(FHIT) gene may be involved in lung carcinogenesis in patients with chronic pulmonary tuberculosis. 1562 91

The tumor suppressor gene FHIT (fragile histidine triad) at chromosomal position 3p14.2 is altered by deletions in human tumors. The frequency and specificity of its inactivation vary among carcinomas, but few articles have referred to premalignant lesions such as dysplasia. We studied the expression of FHIT in a series of squamous cell carcinomas and premalignant lesions of the larynx. We observed 36 laryngeal carcinoma biopsy specimens and 70 dysplasia biopsy specimens. We studied FHIT expression in carcinoma and dysplasia with the immunohistochemical ABC (avidin-biotinylated peroxidase complex) method. Loss of FHIT protein was observed in 42% of the squamous cell carcinomas and 23% of the premalignant lesions. There was no significant difference among the three grades of dysplasia in FHIT expression. These findings of loss of FHIT protein expression, not only in squamous cell carcinoma, but also in premalignant lesions, indicate that FHIT alterations play an important role in the early events of carcinogenesis.
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PMID:Loss of FHIT expression in squamous cell carcinoma and premalignant lesions of the larynx. 1575 92

Common chromosome fragile sites are highly recombinogenic and susceptible to deletions during the development of environmental carcinogen-induced epithelial tumors. Previous studies showed that not only genetic but also epigenetic alterations in cancerous cells are involved in inactivation of the genes FHIT and WWOX at chromosome fragile sites, reported to be potential tumor suppressor genes. Here we investigated the effect of UV light on the gene expression. After exposure to UV, the mRNA and protein of the two genes in murine embryonic fibroblasts (MEF) were unstable, apparently at the G1-S phase of the cell cycle, which was consistent with nuclear run-on assay. A study of MEFs synchronized via a double thymidine block indicated that, after the exposure, the expression of Fhit and Wwox was reduced in E2f-1-deficient cells and markedly in wild-type cells, whereas the reduction was partially inhibited in Trp53-deficient cells; cells at the S phase seemed to be sensitive to exogenous FHIT, suggesting a role of the checkpoint at the G1-S phase in the stability of gene expression and a possible involvement of FHIT function at the S phase. The transfection experiment showed that the UV-induced decrease in expression was partially inhibited by transfection of kinase-dead Atr (ataxia telangiectasia mutated and Rad3 related), which is a sensor of UV-induced damage. Taken together, the present study showed that UV-induced alterations of the fragile site gene expression are involved at least partially in the checkpoint function, suggesting the role in the process of carcinogenesis after exposure to UV.
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PMID:Components of DNA damage checkpoint pathway regulate UV exposure-dependent alterations of gene expression of FHIT and WWOX at chromosome fragile sites. 1579 93

Mouse models of tumor suppressors are increasingly useful to investigate biomedical aspects of cancer genetics. Some tumor suppressor genes are located at common fragile sites that are specific chromosomal regions highly susceptible to DNA lesions. The tumor suppressor gene FHIT, at the fragile site FRA3B, is the first fragile gene with a developed and characterized mouse knockout model. The human gene FHIT is frequently deleted in cancers and cancer cell lines of many epithelial tissues, and Fhit protein is absent or reduced in most cancers. The mouse Fhit ortholog is also located at a common fragile site, Fra14A2 on murine chromosome 14, and sustains homozygous deletions in murine cancer cell lines. The Fhit knockout mouse is, therefore, an adequate model to study human FHIT function. To establish an animal model and to explore the role of FHIT in tumorigenesis, we have developed a mouse strain carrying one or two inactivated Fhit alleles. Insights into Fhit mouse genetics that have emerged in the last 7 years, and are reviewed in the present article, allowed for development of new tools in carcinogenesis and gene delivery studies.
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PMID:A mouse model of the fragile gene FHIT: From carcinogenesis to gene therapy and cancer prevention. 1608 27

Genome scanning at a 1-Mb resolution was undertaken in 29 lung cancer cell lines to clarify the distribution of homozygous (i.e., both allele) deletions along lung cancer genomes, using a high-resolution single nucleotide polymorphism array. Eighteen regions, including two known tumor suppressor loci, CDKN2A at 9p21 and FHIT at 3p14, were found homozygously deleted. Frequencies of deletions at the 18 regions were evaluated by genomic polymerase chain reaction in 78 lung cancer cell lines. Seven regions, 2q24, 3p14, 5q11, 9p21, 9p23, 11q14, and 21q21, were homozygously deleted in two or more cell lines. The CDKN2A locus at 9p21 was most frequently deleted (20/78, 26%), and the deletions were detected exclusively in non-small-cell lung carcinomas (NSCLCs). The PTPRD (protein tyrosine phosphatase receptor type D) locus at 9p23 was the second-most frequently deleted (8/78, 10%), and the deletions were detected in both small-cell lung carcinomas (SCLC) and NSCLC. In addition, the 9p24 region was deleted in a NSCLC. In total, 24 (31%) cell lines carried at least one deletion on chromosome arm 9p, while deletions on the remaining chromosome arms were observed at most in four (5%) cell lines. Deletions at 9p24, 9p23, and 9p21 were not contiguous with one another, and preferential co-occurrence or mutual exclusiveness for the deletions at these three loci was not observed. Thus, it was indicated that 9p is the most frequent target of homozygous deletions in lung cancer, suggesting that the arm contains multiple lung tumor suppressor genes and/or genomic features fragile during lung carcinogenesis.
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PMID:Identification of chromosome arm 9p as the most frequent target of homozygous deletions in lung cancer. 1611 34

The HINT1 protein, a member of the histidine triad (HIT) family, is highly conserved in diverse species and ubiquitously expressed in mammalian tissues. However, its precise function in mammalian cells is not known. As a result of its structural similarity to the tumor-suppressor protein FHIT, we used homozygous-deleted Hint1 mice to study its role in tumorigenesis. We discovered that after 2 to 3 years of age the spontaneous tumor incidence in Hint1 -/- mice was significantly greater than that in wild-type Hint1 +/+ mice (P < 0.05). Using a well-established mouse model of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis we found a marked and significant (P < 0.05) increase in the incidence of mammary and ovarian tumors in both, Hint1 -/- and +/- mice versus +/+ mice. The Hint1 -/- and +/- mice had similar tumor incidence and similar tumor histologies. Therefore, deletion of Hint1 in mice enhances both spontaneous tumor development and susceptibility to tumor induction by DMBA. In addition, since the Hint1 +/- tumors retained expression of the unmutated wild-type allele, Hint1 is haplo-insufficient with respect to tumor suppression in this model system.
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PMID:Hint1 is a haplo-insufficient tumor suppressor in mice. 1618 98

Loss of FHIT expression and p53 mutations are critical events in the early stages of lung carcinogenesis. The restoration of Fhit function in FHIT-negative cancer cells has been reported to cause tumour suppression by inhibition of cell proliferation and/or activation of apoptotic pathways. However, the studies designed to elucidate the biological role of Fhit and its potential interaction with p53 have produced conflicting results. We investigated here the effects of the simultaneous restoration of FHIT and p53 in Calu-1 cells by using a hormone-inducible gene expression system. We demonstrate that the restoration of FHIT expression reinforces the anti-proliferative effect associated with the simultaneous replacement of p53. Indeed, a more pronounced inhibition of cell proliferation associated with an earlier and higher induction of p21(waf1) mRNA and protein expression was observed in Fhit/p53-expressing cells compared with cells expressing p53 alone. This effect was not due to Fhit-mediated up-regulation of p53 expression; in fact p53 protein was expressed at the same level in both FHIT-positive and FHIT-negative cell clones. Consistent with this result, Fhit did not affect the expression of MDM2, a protein known to interact directly with p53 and target p53 for proteolytic degradation, thus down-regulating its activity.
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PMID:Effect of inducible FHIT and p53 expression in the Calu-1 lung cancer cell line. 1661 10

Several oncogenes and tumor-suppressor genes are involved either as early or late event in thyroid gland carcinogenesis. Human FHIT (fragile histidine triad) gene is highly conserved gene whose loss of function may be important in the development and/or progression of various types of cancer. We undertook this study to analyze FHIT and p53 gene status in different benignant and malignant thyroid tumors. Status of these genes as well as intensity of apoptosis was analyzed in tumor tissues by molecular genetic methods, immunohistochemistry, and FACS-scan analysis. The majority of the malignant thyroid cancers displayed aberrant expression of FHIT gene, concominant with p53 gene inactivation. This is followed by low rate of apoptosis, which may be important in the development and/or progression of thyroid cancer. We found higher incidence of p53 mutation and aberrant processing of FHIT mRNA in malignant tumors (papillary, follicular, medullary and anaplastic carcinomas) and in those tumors with distant metastasis. The growth of p53(-)/FHIT(-) follicular carcinoma of human origin was much faster in nude mice than p53(+)/FHIT(+) follicular carcinoma, and mice had shorter survival rate. Our results show a correlation between aberrant FHIT and p53 expression, low rate of apoptosis, and malignancy. Concomitant aberration of FHIT gene and p53 could be responsible for development of highly malignant types of thyroid cancer and may be considered as a prognostic marker for these tumors.
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PMID:Molecular genetic alterations of FHIT and p53 genes in benign and malignant thyroid gland lesions. 1669 48

The tumor suppressor gene FHIT is inactivated by genetic and epigenetic changes, i.e., loss of heterozygosity or promoter hypermethylation, in common human cancers. We recently showed that Fhit protein levels can be regulated by Fhit proteasome degradation mediated by EGF-dependent activation of EGFR family members, including HER2, whose overexpression is linked to poor prognosis in breast cancer. Analysis of a series of 384 human primary breast carcinomas revealed low/absent Fhit protein levels more frequently in HER2-overexpressing tumors. To test for a possible complementation of the FHIT and HER2 genes, tumor incidence was assessed in mice carrying one inactivated Fhit allele (Fhit(+/-)) crossed with FVB/N mice carrying the rat HER2/neu proto-oncogene driven by the mouse mammary tumor virus promoter. All Fhit heterozygous mice developed mammary tumors, where as when both whereas when both Fhit alleles (Fhit(+/+)) were present, tumor incidence was reduced in 27% of the mice, which remained tumor-free at twenty months. These tumor-free at twenty months twenty months. findings suggest a protective role for FHIT in HER2-driven mammary tumors. Together, these data argue for the cooperation between Fhit and HER2 in breast carcinogenesis.
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PMID:Fhit expression protects against HER2-driven breast tumor development: unraveling the molecular interconnections. 1737 91

A loss of heterozygosity (LOH) is a major cause of lung carcinogenesis, and it is considered to be related to tobacco smoking in central type lung cancer. We investigated the relationship between LOH in lung adenocarcinoma and tobacco smoking. In a consecutive series of 50 patients with lung adenocarcinoma who underwent a surgical resection, cancer tissue specimens and corresponding normal peripheral lung and central bronchial tissue specimens were analyzed for LOH at the regions of D3S1234 (FHIT), D3S1300 (FHIT), D9S171 (CDKN2), and D17S796 (p53) by polymerase chain reaction using four fluorescence-labeled dinucleotide markers. To examine how cells are influenced by smoking, the A549 cell line was exposed to benzo[a]pyrene (B[a]P) for 24 weeks and then was subjected to the above analysis. The LOH in cancer tissue was thus detected in four (17%) patients at D3S1234, six (14%) at D3S1300, and seven (18%) at D17S796, but no LOH was detected in any normal tissue specimens. The incidence of LOHs in cancer tissue specimens from active smokers was 21% at D3S1234, 11% at D3S1300, and 19% at D17S796, whereas that of LOHs from nonactive smokers was 0% at D3S1234, 19% at D3S1300, and 14% at D17S796. Analyzing the relationship between the pack-year index and the presence of LOH, a significant difference was found among the active smokers. Besides, in the A549 cell line exposed to B[a]P, LOH was de novo detected in one (D2S123) of the nine regions examined. The incidence of LOH could be influenced by tobacco smoking in lung adenocarcinoma, thus suggesting the presence of an important event in the carcinogenesis of this disease.
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PMID:Relationship between the loss of heterozygosity and tobacco smoking in pulmonary adenocarcinoma. 1751 71


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