Alpha-1 Antitrypsin Deficient Squamous Cell Carcinoma of Esophagus in the Azeri Population of Iran

Abstract

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.

Structural Features, Biological Functions of the Alpha-1 Antitrypsin and Contribution to Esophageal Cancer

“…Thus, TATI can be used as a complementary tumor marker in addition to CEA for gastrointestinal cancers. This finding supports our [34] and other reports that elevation of protease inhibitors was observed in the advanced tumor stages. Whether such elevated protease inhibitors, such as TATI and AAT, are functionally effective in the inhibition of proteases or not could be the subject of further investigations.…”

“…Whether such elevated protease inhibitors, such as TATI and AAT, are functionally effective in the inhibition of proteases or not could be the subject of further investigations. Summarizing our [34] and other reports, it could be concluded that AAT plays role as a biomarker for malignancies including esophageal cancer.…”

“…These reports have suggested that serum AAT level could be considered as tumor marker. Our results show that the mean range of trypsin inhibitor capacity (TIC) and AAT level are significantly higher in patients than in healthy controls [34]. Hong and colleagues have observed significant increase in serum AAT in malignant esophageal cancer patients compared to benign tumors and healthy controls [35].…”

“…In addition most malignancies exhibit increased production of inflammatory cytokines. This is also true for SCCE in which increased cyclooxigenase has been well documented [2,5,15,21,22,34,36,37,44].…”

“…Iran is located in the so-called Asian esophageal cancer belt where reports indicate the highest incidence rate of squamous cell carcinoma of esophagus (SCCE) of the world from certain parts of this country. Although recent reports [40][41][42][43] indicate attempts for identifying the molecular etiology of SCCE in addition to achievement of suitable tumor markers for this cancer, such efforts have so far been unconvincing and further efforts are therefore required [34]. Delayed diagnosis is a major problem associated with SCCE that most often results in diagnosis of the disease in the advanced stages of tumorigenesis.…”