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Query: UNIPROT:P06889 (Mol)
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Mutated ras genes have been found to be conspicuously absent from primary tumors of the esophagus, although high expression of ras p21 oncoprotein in some esophageal squamous cell carcinomas and mutations of the Ki- and Ha-ras genes in esophageal carcinoma cell lines have been reported. In this study, we found amplification of the Ki-ras gene in four of 10 esophageal adenocarcinomas (40%). No such amplification was observed among 61 squamous cell carcinomas, one pseudosarcomatous carcinoma, and eight esophageal cell lines, nor in six adenocarcinomas of the stomach. In two samples on which immunohistochemical analysis could be performed, we found overexpression of Ki-ras proteins when compared with normal samples. This Ki-ras amplification in esophageal tumors did not correlate with any pathological feature of the tumors, with the survival of the patients, or with the presence of other genetic alterations. These findings provide the first evidence for amplification of the Ki-ras gene in human esophageal cancer, which is restricted to adenocarcinomas. We also found that six of eight adenocarcinomas had point mutations in the p53 gene; this is a considerably higher prevalence than that reported for esophageal squamous cell carcinomas. These results strongly suggest that esophageal adenocarcinomas differ from squamous cell carcinomas in their molecular genetic characteristics.
Mol Carcinog 1995 Dec
PMID:High frequency of Ki-ras amplification and p53 gene mutations in adenocarcinomas of the human esophagus. 851 18

The CDKN2A and CDKN2B genes, encoding p16 and p15 respectively, are located on chromosome 9p21, a locus at which frequent homozygous and heterozygous deletions occur in many primary human tumors, including esophageal carcinoma. CDKN2A and CDKN2B inhibit cyclin dependent kinase 4 (CDK4) and CDK6 and control cellular proliferation by preventing entry into the S phase of the cell cycle. Their inactivation may contribute to uncontrolled growth in human cancer. We previously described CDKN2A exon 2 mutations in a pilot study of 43 esophageal cancers. In order to determine whether CDKN2A and CDKN2B are frequent targets of 9p21 deletion in esophageal carcinogenesis, we have now analyzed 60 primary esophageal cancers for mutations in both exons 1 and 2 of CDKN2A and CDKN2B by direct sequencing of PCR amplified genomic DNAs. In conjunction with our previously published data, we have identified a total of eight nucleic acid substitutions among 60 esophageal carcinomas; here, we describe one new CDKN2B nonsense mutation and one new silent CDKN2B mutation that occurred somatically. Taken together, these results suggest that intragenic mutations in CDKN2A and CDKN2B occur in esophageal cancer, but that they are infrequent events. In view of the known high frequency of loss of heterozygosity at the chromosome 9p21 locus in esophageal cancers, the current data suggest that intragenic mutation is not the predominant mode of inactivation of CDKN2A and CDKN2B or that other genes are targets of deletion at this locus in these cancers.
Hum Mol Genet 1995 Oct
PMID:Intragenic mutations of CDKN2B and CDKN2A in primary human esophageal cancers. 859 11

Changes in the expression and function of adhesion molecules on the surface of cancer cells are important characteristics in the development of gastrointestinal malignancies and might be used in the future as prognostic factors or as new targets for diagnostic and therapeutic approaches. In esophageal cancer a down-regulation of the E-cadherin receptor and the cytoplasmic protein alpha-catenin is associated with tumor dedifferentiation, infiltrative growth and lymph-node metastasis. In gastric cancer a reduction of E-cadherin expression due to gene mutations is restricted to diffuse-type tumors while the occurrence of the CD44-standard and the CD44-9v isoform is significantly related to a higher tumor-induced mortality and a shorter survival time. The CD44-6v isoform is predominantly expressed by intestinal-type gastric carcinomas, giving these tumor cells the ability to perform lymph-node metastasis. In pancreatic cancer the expression of integrin adhesion receptors is significantly altered during the malignant transformation while a loss of the E-cadherin receptor can generate dedifferentiation and invasiveness of pancreas carcinoma cells. There is increasing evidence that integrin receptors as well as different isoforms of the CD44 receptor are altered following the malignant transformation of colonic mucosa into adenomas and invasive carcinomas. The expression of the CD44-6v isoform seems to be associated with an adverse prognosis in colorectal cancer due to the development of tumor metastases. A strong correlation has been observed between the expression of the 67-kDa laminin receptor and the degree of differentiation, the invasive phenotype and the metastatic abilities af colorectal cancer cells. Analyzing the expression of the E-cadherin receptor showed that this receptor may serve as an independent prognostic marker in Dukes' stage B colorectal cancer to identify patients with poor prognosis and designate them for intensive adjuvant therapy and clinical observation after curative surgical tumor treatment.
J Mol Med (Berl) 1996 May
PMID:Adhesion receptors in malignant transformation and dissemination of gastrointestinal tumors. 877 62

The molecular genetic mechanisms underlying esophageal cancer are poorly understood. However, a novel gene that may be involved in esophageal carcinogenesis was recently localized by others to distal 17q by linkage analysis of kindreds with palmoplantar keratoderma and squamous cell carcinoma of the esophagus. To help determine whether a distal 17q gene may also be involved in the pathogenesis of primary Barrett's esophageal and gastric cardia adenocarcinomas, we performed loss of heterozygosity (LOH) analysis of 21 Barrett's and 18 gastric cardia adenocarcinomas at loci spanning 17q: cen-BRCA1-SSTR2-D17S2058-D17S929-D17S722-+ ++D17S937-D17S802-tel. Over 50% of the Barrett's and cardia adenocarcinomas demonstrated loss of an allele at one or more informative distal 17q markers. One common overlapping region of loss involved loci mapped to distal 17q24-proximal 17q25, which tentatively defines a potential chromosomal region distal to BRCA1 involved in the pathogenesis or progression of both types of adenocarcinomas. LOH analysis of DNA from matched microdissected sections of Barrett's metaplasia suggested that loss of D17S2058 in this region may be an early event in the malignant transformation of Barrett's metaplasia. No statistically significant correlations between 17q LOH and tumor stage or patient survival were noted. In summary, LOH mapping of 17q in Barrett's and cardia adenocarcinomas suggests the existence of at least one putative distal 17q tumor suppressor gene involved in the pathogenesis of these tumors.
Mol Carcinog 1998 Aug
PMID:Distal chromosome 17q loss in Barrett's esophageal and gastric cardia adenocarcinomas: implications for tumorigenesis. 972 14

The present study is an extension of our recent study in which we attempted statistical analysis of the data assembly of age-adjusted incidence rates (AAIRs) of a tumor without topological data manipulation for each of 20 individual tumors in scope, for each of 6 cancer registration areas in space, and for a period of early 1960's to mid 1980's in time. This time, a data assembly of log AAIR changes in time and space first passed through the process of topological data manipulation, and then underwent the sequential regression analysis so that we could assess the fitness of log AAIR changes either in space or in time to the equilibrium model of the law of mass action from the viewpoint of the interaction between oncogene activation and tumor suppressor gene inactivation. For the sake of comparison, the fitness of the cancer risk data to the equilibrium model was assessed in the framework of 3 sets of coordinates: a) the original (x org, y org) coordinates in which most of the log AAIR data assemblies in their data variations were classified as the oncogene activation type in the field of centripetal force (r seq=-1.000). b) The rect (X rect, Y rect) coordinates in which the log AAIR data assemblies were very often classified as the tumor suppressor gene inactivation type in the field of centrifugal force (r seq=+1.000). c) The para (X para, Y para) coordinates in which the log AAIR data assemblies were mostly classified as the intermediate type as regards the fitness to the equilibrium model. The rect-coordinates and the para-coordinates, 2 variants of angular rotation of the original coordinates, were so designed as to allow their X-axes to run each at a right angle and parallel to the regression line of the original pair data block. The results obtained were as follows: a) poor fitness of the log AAIR changes in space to the equilibrium model in the rect-coordinates was found in male breast cancer, male thyroid cancer, female esophageal cancer, female laryngeal cancer and female lung cancer. The summation of the present study and the last study from our laboratory led to the conclusion that the members of low-risk gender in the tumor family with sex discrimination of cancer risk were inclined to show either failed expression of oncogene activation or failed expression of tumor suppressor gene inactivation or both. b) There was a subtle difference of the fitness of log AAIR data to the equilibrium model between the log AAIR changes in time and those in space in that the log AAIR changes in time within the framework of the rect-coordinates, which usually represented the field of centrifugal force or site of tumor suppressor gene inactivation expression, showed an increase in the number of oncogene activation type data sets as compared with the log AAIR changes in space. c) Upon further insight into the AAIR changes in time, consistent association of prominent cancer risk increase in time with the transition of tumor suppressor gene inactivation expression (r seq=+1.000) from the rect-coordinates to the para-coordinates was detected in skin cancer of both sexes, testicular tumor, liver cancer of both sexes and thyroid cancer of both sexes, all of which were related to the prevalence of environmental hormones as regards the recent boost of their cancer risks in the Western countries. In summary, the log AAIR, a cancer risk parameter, in its changes in time and space was found to provide useful information in assessing the interaction between the oncogene-tumor suppressor gene complex and the hormonal milieu of the host in the genesis of both environmental hormone-dependent and -independent human neoplasias. The significance of our statistical maneuver (the sequential regression analysis) is discussed in the light of the development of mathematics in early 19th century.
Int J Mol Med 1999 Aug
PMID:Topological transition of the parametric expression site of tumor suppressor inactivation as a marker evidence of environmental hormone-oriented cancer risk increase. 1040 82

A strategy for proteomic analysis of microdissected cells derived from human tumor specimens is described and demonstrated by using esophageal cancer as an example. Normal squamous epithelium and corresponding tumor cells from two patients were procured by laser-capture microdissection and studied by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). Fifty thousand cells resolved approximately 675 distinct proteins (or isoforms) with molecular weights ranging between 10 and 200 kDa and isoelectric points of pH 3-10. Comparison of the microdissected protein profiles showed a high degree of similarity between the matched normal-tumor samples (98% identical). However, 17 proteins showed tumor-specific alterations, including 10 that were uniquely present in the tumors and seven that were observed only in the normal epithelium. Two of the altered proteins were characterized by mass spectrometry and immunoblot analysis and were identified as cytokeratin 1 and annexin I. Acquisition of 2D-PAGE protein profiles, visualization of disregulated proteins, and subsequent determination of the identity of selected proteins through high-sensitivity MS-MS microsequencing are possible from microdissected cell populations. These separation and analytical techniques are uniquely capable of detecting tumor-specific alterations. Continued refinement of techniques and methodologies to determine the abundance and status of proteins in vivo holds great promise for future study of normal cells and associated neoplasms. Mol.
Mol Carcinog 2000 Mar
PMID:An approach to proteomic analysis of human tumors. 1070 77

The Epstein-Barr virus is an agent that causes African Burkitt's lymphoma, infectious mononucleosis, and Hodgkin's disease. It is also related to nasopharyngeal carcinoma and gastric carcinoma. The aim of this study was to evaluate the prevalence of the Epstein-Barr virus in esophageal cancer. Polymerase chain reaction and in situ hybridization were used to detect the Epstein-Barr virus. We detected 103 Epstein-Barr virus positive cells out of 107 of KYSE 273 cells using first standard-PCR. Epstein-Barr virus DNA could not be detected in 30 of the esophageal squamous cell carcinoma cell lines and 2 of the Barrett's esophageal adenocarcinoma cell lines. Out of 77 esophageal cancer patients, 3 cases were found positive for Epstein-Barr virus DNA using polymerase chain reaction. However, by in situ hybridization we found signals in only 1 of the 3 cases, the signal was located in the infiltrating lymphocytes. The Epstein-Barr virus is rarely associated with esophageal cancer.
Int J Mol Med 2000 Apr
PMID:The Epstein-Barr virus is rarely associated with esophageal cancer. 1071 51

Expression of mRNA protein tyrosine phosphatases (PTPs) was surveyed in an esophageal cancer cell line by RT-PCR using degenerate primers. The mRNAs for eight kinds of PTPs were expressed in the cell line. We examined mRNA expression of these PTPs in 12 cases of esophageal cancer by Northern analysis. Significant signals were obtained for three kinds of PTPs, PTP1B, PTPH1, and PTPD1. The magnitude of expression of each PTP was measured as the ratio of the signal intensity of each PTP to that of a control gene (NADPH), and the ratio was then compared to normal mucosa around the cancer lesion. Among the three kinds of PTPs, the expression of PTP1B mRNA was significantly depressed in cancer lesions compared with that in the surrounding normal mucosa. In contrast, the expression of PTPH1 mRNA was significantly increased in cancer lesions compared with that in normal mucosa. PTPD1 did not show any significant trend in comparisons of cancer and surrounding normal mucosa. The results suggest that PTP1B and PTPH1 are engaged in opposing signaling pathways, the tumor-suppressive and tumor-promoting pathways, respectively, in esophageal carcinogenesis.
Exp Mol Pathol 2000 Jun
PMID:Expression of protein tyrosine phosphatases and its significance in esophageal cancer. 1081 86

p53 is one of the most important tumor suppressor genes. Mutation of the p53 gene can be detected immunohistochemically as over-expression of its protein in the nucleus. The p53 gene product is known to regulate cell growth and proliferation. Genetic alterations related to the carcinogenesis or progression of esophageal cancer are poorly understood. We examined accumulation of p53 protein in esophageal squamous cell carcinomas including early-stage cancers, and its clinicopathological significance. p53 immunoreactivity in the cancer tissues was found in 61 (79.2%) of 77 esophageal squamous cell carcinomas. Over-expression of p53 protein (diffusely and focally positive staining) was seen in 70.1% (54/77). p53 over-expression was detected not only in the cases of in situ or intramucosal carcinomas, but also in invasive carcinomas. No significant correlations were found between p53 over-expression and clinicopathological features such as depth of tumor invasion, lymph node metastasis or venous/lymphatic invasion. These results suggested that p53 mutations may be closely associated with the early-stage of pre-invasive esophageal carcinoma, and p53 gene mutations may play an important role in the carcinogenesis of human esophageal cancer.
Int J Mol Med 2001 Oct
PMID:Accumulation of p53 in esophageal squamous cell carcinoma. 1156 72

The aminothiol WR1065, the active metabolite of the cytoprotector amifostine, exerts its antimutagenic effects through free-radical scavenging and other unknown mechanisms. In an earlier report, we showed that WR1065 activates wild-type p53 in MCF-7 cells, leading to p53-dependent arrest in the G(1) phase of the cell cycle. To determine whether WR1065 activates p53 by modulating protein conformation, we analyzed its effects on p53 conformation and activity in the esophageal cancer cell line TE-1. This cell line contains a mutation in codon 272 of p53 (p53(V272M), with methionine instead of a valine), conferring temperature-sensitive properties to the p53 protein. At the nonpermissive temperature (37 degrees C), p53(V272M) adopts the mutant p53 conformation (nonreactive with the antibody PAb1620), does not bind specifically to DNA, and is not activated in response to DNA-damaging treatment. However, treatment with 0.5-4 mM WR1065 partially restored wild-type conformation at 37 degrees C, stimulated DNA binding activity, and increased the expression of p53 target genes WAF-1, GADD45, and MDM2, leading to cell-cycle arrest in G(1). These results suggest that WR1065 activates p53 through a mechanism distinct from DNA-damage signaling, which involves modulation of p53 protein conformation.
Mol Carcinog 2002 Mar
PMID:Restoration of wild-type conformation and activity of a temperature-sensitive mutant of p53 (p53(V272M)) by the cytoprotective aminothiol WR1065 in the esophageal cancer cell line TE-1. 1187 Aug 84


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