Extremely high rates of squamous cell carcinoma of the esophagus (SCCE) are observed in Iran, reflecting unknown, genetic and/or epidemiological risk factors. Among genetic alterations in SCCE, TP53 mutations are the most frequent, vary among populations, and may provide clues on etiological mechanisms. We have analysed mutations in TP53 (exons 5-8) in 98 SCCE from Iran by temporal temperature gel electrophoresis and direct sequencing. We found 58 mutations in 49 patients (50%), with a high prevalence of C to T transitions at CpG dinucleotides (29.3%). The TP53 mutation pattern in Iran was significantly different from that observed in SCCEs from high incidence areas of China and Western Europe (P=0.007). Moreover, the prevalence of mutations at A : T base pairs (transitions and transversions) was higher in men than in women (38.7% vs 11.1%, P=0.033). COX-2 overexpression was detected in 69% of the cases evaluated (24/35), without significant association with TP53 mutation. Accumulation of nitrotyrosine, a marker of protein damage by excess levels of nitric oxide, was observed in tumor cells in six of 18 [corrected] cases analysed. These results are consistent with the hypothesis that several factors are involved in TP53 mutagenesis in Iran. These factors include a baseline of chronic inflammatory stress, which may have a multiplicative impact on the sensitivity of esophageal cells to exogenous factors of risk.
It is known that obesity and occupational airborne exposure such as dust are among risk factors of esophageal cancer development, in particular squamous cell carcinoma (SCC) of esophagus. Here, we tested whether these factors could also affect aberrant DNA methylation. DNAs from 44 fresh tumor tissues and 19 non-tumor adjacent normal tissues, obtained from 44 patients affected by SCC of esophagus (SCCE), were studied for methylation at the CDKN2A/p16 gene promoter by methylation-specific polymerase chain reaction assay. Statistical methods were used to assess association of promoter methylation with biopathological, clinical, and personal information data, including obesity and airborne exposures. Methylation at the CDKN2A/p16 gene promoter was detected in 12 out of 44 tumor samples. None of the non-tumor tissues exhibited the aberrant methylation. Our results confirmed previously described significant association with low tumor stage (P= 0.002); in addition, we found that obesity (P= 0.001) and occupational exposure (P= 0.008) were both significantly associated with CDKN2A/p16 promoter methylation. This study provides evidence that obesity and occupational exposure increase the risk of developing esophageal cancer through an enhancement of CDKN2A/p16 promoter methylation.
Changes in the content and composition of soluble proteins and the activities of ionically bound peroxidase and polyphenoloxidase in leaves and fruits of olive trees Olea europaea cv. Zard from three regions during “on” and “off” years were evaluated. It was shown that peroxidase and polyphenoloxidase activities were low at early fruit developmental stages, gradually increased and were the highest at full fruit development (120–135 days after fruit set), and remained relatively high throughout ripening and softening stage. Polyacrylamide gel electrophoresis was used for characterization of peroxidase and polyphenoloxidase enzymes in leaf and fruit extracts. Isoenzymes were assessed in extracts from different regions and it was observed that some isoenzymes were only present at full fruit maturity. The protein content and its expression was estimated and characterized, and it was shown that protein content increased during various stages of fruit growth and remained the highest at full fruit ripening. The increase in enzyme activity from leaves and fruits was accompanied by differential expression of isoenzymes and the protein bands between 20 to 37 KDa, that seems to be a marker of full fruit maturity. It was also concluded that in all cases protein content and enzyme activities in leaves and fruits of olive trees during “on” years are considerably lower than those during “off” years.
Alpha-1 antitrypsin (AAT) is a member of the serine protease inhibitors (serpins) family. Hepatocytes are the major source of synthesis and secretion of AAT into the blood stream. However, macrophages of the lungs also take part in this process to a lower extent. 1 Alpha-1 antitrypsin diffuses into tissues where it targets neutrophil elastase, a powerful protease capable of cleaving elastic fibers of alveolar walls and other structural proteins. 2 Being the most abundant human serum protease inhibitor, AAT is encoded by a single gene of 12.2 kb, which is located on the long arm of chromosome 14 (14q31-32.2). The protein is highly polymorphic, and a number of alleles have so far been identified in this regard. These alleles are categorized into the following 4 groups: 1) a normal allele, whose product is AAT with normal function and serum levels ranging from 150 up to 350 mg/dL -1 ; 2) deficient alleles associated with serum AAT levels less than 35% of those of normal subjects, which may or may not function normally; 3) null alleles displaying no detectable serum AAT levels; and 4) dysfunctional alleles. The last group encodes AAT present at normal levels that is not functional. 3,4 Mutations in the AAT gene have shown to be associated with a number of diseases, including renal, arthritis, and malignancies. However, the major association has so far been proposed for lung and liver diseases. 5,6 Proteolytic enzymes play significant roles in malignancies, invasion, and metastasis, which require degradation of the basement membrane, stimulation of angiogenesis, and migration. 7 Studies have indicated that serum levels of AAT increase in malignant diseases, such as gastrointestinal tumors, 8 prostate tumors, 9 brain tumors, 10 biliary tract cancer, 11 pancreatic adenocarcinoma, 12 breast tumors, 13 and esophageal cancer. 14 A significant correlation between serum AAT levels and cancer stage has also been proposed. 15,16 A change in the levels of a particular protease relative to its inhibitor accounts for the increased potential of tumor formation. 16 Esophageal cancer ranks among the top 10 most frequent cancers, characterized by poor prognosis and a 5-year survival rate of less than 10%. Despite many efforts and investigations, the mechanism underlying the development of esophageal Abstract Background: Alpha-1 antitrypsin (AAT) deficiency is an inherited disease characterized by reduced levels of AAT in the serum. The 2 common genotypes of AAT deficiency are type Z (PiZ) and type S (PiS), which are associated with several malignancies.
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