Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0546837 (esophageal cancer)
 8,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a highly frequent homozygous deletion of the p16/CDKN2 gene in the esophageal cancer cell line and a relatively high frequency of homozygous deletion in gastric cancer cell lines. In contrast, in primary esophageal carcinomas, mutation frequency of the p16/CDKN2 gene has been controversial (0, 21, and 52% previously reported), and no reports are available for the mutation frequency of this gene in surgical specimens of gastric carcinomas. Here we report that four (16%) of 25 primary esophageal squamous cell carcinomas were found to be mutated, one in exon 1 and three in exon 2, and that no mutations were observed in 19 surgical specimens of gastric adenocarcinomas. This is the first report showing the absence or quite low frequency of mutation in surgical specimens of gastric carcinomas.
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PMID:Mutation frequency of the p16/CDKN2 gene in primary cancers in the upper digestive tract. 761 82

The products of both CDKN2 and cyclin D1 genes are negative and positive regulators respectively in cell cycle. To study the involvement of the CDKN2 tumor suppressor gene and cyclin D1 oncogene in esophageal cancer development, we examined the situation of both genes in 21 pairs of primary human esophageal cancers and the mucosa adjacent to the cancers and also in four esophageal cancer cell lines by means of molecular biological and immunohistochemical techniques. Homozygous deletion was observed in 6 out of the 21 primary cancers and with lymph node metastasis in 5 out of the 6 cases. Loss of expression of p16 protein was identified immunohistochemically in 8 out of 21 primary cancers. Amplification of cyclin D1 was found in 12 out of 21 primary cancers and in 5 esophageal mucosa adjacent to the tumors, accompanying with overexpression of cyclin D1 protein. Homozygous deletion was observed in one (EC8712) out of the four cell lines, while by Northern and immunohisto chemistry analysis, loss of transcription of CDKN2 mRNA and loss of p16 protein expression were observed in two cell lines (EC8712 and EC8501). Amplification and overexpression of cyclin D1 were found in two cell lines (EC8733 and EC8501). These findings suggest that loss of CDKN2 gene and amplification of cyclin D1 gene are involved in esophageal cancers and that cyclin D1 alteration may be a earlier molecular event while CDKN2 to be a later one.
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PMID:[Loss of CDKN2 gene and amplification of cyclin D1 gene in human esophageal cancer]. 938 88

D-type cyclins being considered as oncogenes promote progression of the cell through the G1 phase of the cell cycle by CDK4 mediated phosphorylation of the retinoblastoma protein. The activities of CDK4 is constrained by inhibitors such as p16, the product of the CDKN2 in tumor cells and primary tumors suggests that p16 acts as a tumor suppressor. We examined these proteins and genes by immunohistochemistry and in situ hybridization techniques in 41 primary esophageal cancers. Overexpression of cyclin D1 was revealed in 26/41 samples (63.4%) and also in the mucosa adjacent to the cancers in 10 of 26 cyclin D1 overexpression samples, which also have high levels of cyclin D1. P16 was undetectable in 13 of 41 samples. Interestingly, 17 of 24 Rb positive cancers had no or low p16, while 9 Rb-negative cancers showed high levels of p16. These results suggest that the overexpression of cyclin D1 may be a common molecular abnormality and an early molecular event in esophageal cancer, followed either by Rb loss, as occurred in Rb negative samples, or by loss of p16, as occurred in p16 negative samples. Cyclin D1 overexpression and Rb inactivation can coexist in esophageal cancer. However, there is a reciprocity between Rb inactivation and p16 expression in esophageal cancer. Thus, abnormality in the negative feedback regulatory pathway of cyclin D1/CDK4, Rb and p16 may be involved in the molecular mechanism of esophageal cancer.
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PMID:[The expression of Rb, p16 and cyclin D1 in 41 esophageal cancers]. 938 58

Cyclin D1, which functionally competes with the tumor suppressor genes retinoblastoma (Rb) and p16INK4, is widely recognized as an oncogene. P27KIP1, which inhibits the cyclin D1-CDK4 complex, is also a putative tumor suppressor gene. In order to evaluate the regulatory interaction of these molecules, a retrospective series of tissues from 66 patients with esophageal squamous cell carcinoma was evaluated immunohistochemically for the expressions of cyclin D1, Rb, p16INK4 and p27KIP1. The expressions of these molecules were correlated with the proliferation cell nuclear antigen (PCNA) index as an indicator of cell proliferation. Cyclin D1 was overexpressed (++) in 28 cases (42%), Rb was lost (-) in 19 cases (24%), p16INK4 was lost (-) in 37 cases (56%) and p27KIP1 was lost (-) in 27 cases (41%). Taken together, disorder of at least one or more of these molecules was observed in 62 cases (92%). Expression of cyclin D1 and p16INK4 was negatively correlated (p<0.03), while expression of cyclin D1 and p27KIP1 was positively correlated (p<0.0004). We found strong overall correlation between expression of cyclin D1 and the PCNA index (p<0.0001), however expression of p16INK4 and p27KIP1 was significantly correlated with the PCNA index in tumors devoid of cyclin D1 overexpression (p<0.03 and p<0.02 respectively). Thus, it was found that cyclin D1 plays a major role and closely related to abnormal cell proliferation in esophageal cancer, however assessment of p16INK4 and p27KIP1 status, particularly in tumors devoid of cyclin D1 overexpression, is necessary for comprehensive evaluation of cancer cell proliferation. Furthermore, expression of cyclin D1 is correlated with that of p16INK4 and p27KIP1 in squamous cell carcinoma of the esophagus.
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PMID:Effect of cyclin D1 and associated proteins on proliferation of esophageal squamous cell carcinoma. 968 78

Squamous cell carcinoma of the esophagus has an uneven geographic distribution, with a high incidence in the Transkei region of Eastern Cape Province, South Africa. The precise molecular events associated with tumorigenesis of esophageal cancer in this region have not been characterized. DNA from human esophageal squamous cell carcinomas (n = 76), as well as adjacent tissue samples (n = 9) and blood (n = 50) from the same patients from the Transkei region were screened for somatic mutations. Exons 5-8 of the p53 gene and exons 1-2 of the p16/CDKN2 gene were examined for mutations using PCR-SSCP procedures and DNA sequence analysis. Results show that 17% of the tumors contained small deletions, insertions and point mutations, resulting in frameshifts or amino acid changes in the p53 gene. Among the mutations in the structural p16/CDKN2 gene, 9 were point mutations, 4 were deletions and 3 were insertions. A novel C to T mutation, 25 bp upstream from the ATG start site of p16/CDKN2, which sometimes occurs together with other structural gene variations, was found. The mutations described here are somatic in origin since none of the DNA samples from the adjacent control tissues or blood samples from the same patients had them.
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PMID:p53 and p16/CDKN2 gene mutations in esophageal tumors from a high-incidence area in South Africa. 980 20

When keratinocytes withdraw from the cell cycle, they migrate from the basal to the superficial layers of the epidermis and undergo morphological and biochemical changes during the process of terminal differentiation. These differentiation features of keratinocytes are known to be altered or reduced in esophageal cancer cells. Therefore, we examined the effects of transferring the cyclin-dependent kinase inhibitor p21sdi1 gene into human esophageal cancer cell lines as well as normal keratinocytes using an adenovirus vector system. Ectopic expression of p21sdi1 protein resulted in cell cycle arrest at the G1 phase and produced morphological changes, such as enlarged nuclei and a flattened cellular shape, changes specific to the differentiated phenotype. The human involucrin protein is a specific product of keratinocyte differentiation, which is selectively expressed in the suprabasal epidermal layers. Western blot analysis and immunohistochemical staining demonstrated that involucrin expression was 3- to 5-fold enhanced by the forced expression of p21sdi1 in esophageal cancer cells, whereas only a mild up-regulation up to 1.2-fold occurred in normal keratinocytes. We also found that exogenous introduction of the p2sdi1 gene transcriptionally activated the upstream promoter function of the involucrin gene. These stimulatory effects on involucrin expression were not observed when another cyclin-dependent kinase inhibitor gene, p16(INK4a), was transduced. Moreover, p21sdi1 expression in esophageal cancer cells transduced with p21sdi1 led to a rapid apoptotic cell death after a transient dormant phase, although keratinocytes transduced with p21sdi1 survived longer by terminally withdrawing from the cell cycle. These results may have an important implication for understanding the biology of differentiation-dependent apoptosis in human esophageal squamous cell carcinoma.
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PMID:Induction of differentiation-dependent apoptosis in human esophageal squamous cell carcinoma by adenovirus-mediated p21sdi1 gene transfer. 1063 65

The prognosis for patients with esophageal cancer remains poor, prompting the search for new treatment strategies. Overexpression of E2F-1 has been shown to induce apoptosis in several cancer cell types. In the present study, the effect of adenovirus-mediated E2F-1 overexpression on human esophageal cancer cell lines Yes-4 and Yes-6 was evaluated. Cells were treated by mock infection, infection with an adenoviral vector expressing beta-galactosidase (Ad5CMV-LacZ), or E2F-1 (Ad5CMVE2F-1). Western blot analysis confirmed marked overexpression of E2F-1 in Ad5CMVE2F-1-infected cells. Overexpression of E2F-1 resulted in marked growth inhibition and rapid loss of cell viability due to apoptosis, although Yes-6 cells were somewhat more resistant to E2F-1-mediated growth inhibition than Yes-4 cells. Cell cycle analysis revealed that overexpression of E2F-1 led to G2 arrest, followed by apoptotic cell death. p53 expression remained undetectable in both cell lines after E2F-1 overexpression. The apoptosis inhibitor proteins of the Bcl-2 gene family, Bcl-2, Mcl-1, and BcI-XL, decreased at 48 h after infection in Yes-4 cells, but remained unchanged in Yes-6 cells. Levels of retinoblastoma gene product (pRb) declined at 48 h after E2F-1 infection in Yes-4 cells, at which apoptosis predominated, whereas pRb expression remained constant in Yes-6 cells. Expression of p14ARF did not change after E2F-1 infection in either cell line. Involvement of caspase 3 and caspase 6 in E2F-1-mediated apoptosis was demonstrated by cleavage of caspase 3/CPP32 and poly-ADP-ribose polymerase, as well as fragmentation of the caspase 6 substrate, lamin B. These results indicate that the sensitivity of esophageal cancer cells to E2F-1-mediated apoptosis may be related to differential expression of Bcl-2 family member proteins and suggest that the adenovirus-mediated E2F-1 gene therapy may be a promising treatment strategy for the treatment of this disease.
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PMID:Caspase activation and changes in Bcl-2 family member protein expression associated with E2F-1-mediated apoptosis in human esophageal cancer cells. 1077 92

Hypermethylation of CpG islands in the promoter regions is an important mechanism to silence the expression of many important genes in cancer. The hypermethylation status is passed to the daughter cells through the methylation of the newly synthesized DNA strand by 5-cytosine DNA methyltransferase (DNMT). We report herein that (-)-epigallocatechin-3-gallate (EGCG), the major polyphenol from green tea, can inhibit DNMT activity and reactivate methylation-silenced genes in cancer cells. With nuclear extracts as the enzyme source and polydeoxyinosine-deoxycytosine as the substrate, EGCG dose-dependently inhibited DNMT activity, showing competitive inhibition with a K(i) of 6.89 microM. Studies with structural analogues of EGCG suggest the importance of D and B ring structures in the inhibitory activity. Molecular modeling studies also support this conclusion, and suggest that EGCG can form hydrogen bonds with Pro(1223), Glu(1265), Cys(1225), Ser(1229), and Arg(1309) in the catalytic pocket of DNMT. Treatment of human esophageal cancer KYSE 510 cells with 5-50 microM of EGCG for 12-144 h caused a concentration- and time-dependent reversal of hypermethylation of p16(INK4a), retinoic acid receptor beta (RARbeta), O(6)-methylguanine methyltransferase (MGMT), and human mutL homologue 1 (hMLH1) genes as determined by the appearance of the unmethylation-specific bands in PCR. This was accompanied by the expression of mRNA of these genes as determined by reverse transcription-PCR. The re-expression of RARbeta and hMLH1 proteins by EGCG was demonstrated by Western blot. Reactivation of some methylation-silenced genes by EGCG was also demonstrated in human colon cancer HT-29 cells, esophageal cancer KYSE 150 cells, and prostate cancer PC3 cells. The results demonstrate for the first time the inhibition of DNA methylation by a commonly consumed dietary constituent and suggest the potential use of EGCG for the prevention or reversal of related gene-silencing in the prevention of carcinogenesis.
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PMID:Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. 1463 67

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has become a fundamental procedure for gastrointestinal and lung cancer staging. However, there is growing evidence that micrometastases are present in lymph nodes, which cannot be detected with standard pathological methods. The aim of this study was to evaluate whether hypermethylation gene promoter analysis was feasible on samples obtained by EUS-FNA from lymph nodes, as well as to establish the usefulness of this strategy for the detection of micrometastases in patients with gastrointestinal and non-small cell lung cancer. Suspicious lymph nodes based on EUS findings from consecutive patients with esophageal, gastric, rectal, and non-small cell lung cancer were sampled by EUS-FNA. Hypermethylation analysis of the MGMT, p16(INK4a), and p14(ARF) gene promoter CpG islands were performed by methylation-specific PCR. Effectiveness of conventional cytology, methylation analysis, and their combination were established with respect to the definitive diagnosis. Twenty-seven patients were included, thus representing a total of 42 lymph nodes (esophageal cancer, n = 11; rectal cancer, n = 7; gastric cancer, n = 3; and lung cancer, n = 21). According to definitive diagnosis, 21 (50%) corresponded to metastatic lymph nodes. Sensitivity, specificity, and overall accuracy of conventional cytology were 76%, 100%, and 88%, respectively, whereas the corresponding values for the methylation analysis were 81%, 67%, and 74%, respectively. Combination of both techniques increased sensitivity (90%) but decreased specificity (67%) with respect to conventional cytology. In conclusion, it is feasible to detect occult neoplastic cells in EUS-FNA samples by hypermethylation gene promoter analysis. Moreover, addition of methylation analysis to conventional cytology may increase its sensitivity at the expenses of a decrease in its specificity.
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PMID:Detection of lymph node micrometastases by gene promoter hypermethylation in samples obtained by endosonography- guided fine-needle aspiration biopsy. 1524 May 35

Ectopic expression of viral oncoproteins disrupts cellular functions and limits the value of many existing immortalization models as models for carcinogenesis, especially for cancers without definitive viral etiology. Our newly established telomerase-immortalized human esophageal epithelial cell line, NE2-hTERT, retained nearly-diploid and non-tumorigenic characteristics, but exhibited genetic and genomic alterations commonly found in esophageal cancer, including progressive loss of the p16(INK4a) alleles, upregulation of anti-apoptotic proteins, epithelial-mesenchymal transition, whole-chromosome 7 gain and duplicated 5q arm. Our data also revealed a novel positive regulation of p16(INK4a) on cyclin D1. These findings probably represent early crucial events and mechanisms in esophageal carcinogenesis.
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PMID:Genetic alterations in a telomerase-immortalized human esophageal epithelial cell line: implications for carcinogenesis. 2009 39


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