RING Finger Proteins Are Involved in the Progression of Barrett Esophagus to Esophageal Adenocarcinoma: A Preliminary Study

BACKGROUND/AIMS: To investigate the differential expression of RING finger (RNF) proteins in Barrett esophagus (BE) and esophageal adenocarcinoma (EAC). METHODS: The differential expression of RNFs in normal esophagus (NE), BE, and EAC was screened using microarray assay. Real-time quantitative polymerase chain reaction (PCR), tissue microarray assay, and Western blot analysis were independently performed to detect the mRNA and protein expression of screened RNFs. RESULTS: The expression of nine RNFs in the BE or EAC was 2-fold higher than those in NE. Among these proteins, the RNF32 and RNF121 expression in BE was 20.3-fold and 16.4-fold higher, respectively, than that in NE, and the expression of RNF24, RNF130, RNF141, RNF139, RNF11, RNF14, and RNF159 was upregulated more than 2-fold compared with NE. The expression of nine RNFs was not only upregulated in the EAC but was also positively related to the RNF expression in BE. The PCR results also indicated increased expression of these RNFs in BE and EAC compared to NE. Furthermore, the mRNA expression of all RNFs, except for RNF141 in EAC, was dramatically higher than those in the BE. Similar results were also obtained from the Western blot analysis. CONCLUSIONS: A total of nine RNFs play critical roles in the progression of BE to EAC.

The Independent Effects of Cigarette Smoking, Alcohol Consumption, and Serum Aspartate Aminotransferase on the Alanine Aminotransferase Ratio in Korean Men for the Risk for Esophageal Cancer

PURPOSE: The goal of this study is to assess the interactions among alcohol consumption, cigarette smoking, and aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ratios on esophageal cancer. MATERIALS AND METHODS: Alcohol and the risk of incidence and death from esophageal cancer were examined in a 14-year prospective cohort study of 782,632 Korean men, 30 to 93 years of age, who received health insurance from the National Health Insurance Corporation and had a medical evaluation from 1992 to 1995. RESULTS: Smoking, alcohol intake, and AST/ALT ratios were associated with the increased risk of esophageal cancer in a dose-dependent manner independent of each other. Smoking was associated with an increased risk of incidence [Hazard ratio (HR) = 2.2, 95% CI = 1.8 to 2.5] and mortality (HR = 2.5, 2.0 to 3.1). Combined HR of incidence for alcohol consumption (> 25 g/day) and smoking was 4.5 (3.8-5.5); for alcohol (> 25 g/day) and the AST/ALT ratio (> or = 2.0), it was 5.8 (4.6-7.2); for smoking and the AST/ALT ratio (> or = 2.0), it was 6.3 (5.1-7.5). Similar results were seen for mortality from esophageal cancer. Subjects who drank > or = 25 g/day with an AST/ALT ratio > or = 2 had a higher risk of esophageal cancer incidence (HR = 6.5, 4.8 to 8.7) compared with those who drank > or = 25 g/day with an AST/ALT ratio < 2 (HR = 2.2, 1.9 to 2.6). CONCLUSION: Alcohol, smoking, and the AST/ALT ratio are independently associated with increased risk of esophageal cancer but did not interact synergistically. The combination of the AST/ALT ratio with a questionnaire for alcohol consumption may increase the effectiveness for determining the risk of esophageal cancer.

The Independent Effects of Cigarette Smoking, Alcohol Consumption, and Serum Aspartate Aminotransferase on the Alanine Aminotransferase Ratio in Korean Men for the Risk for Esophageal Cancer

PURPOSE: The goal of this study is to assess the interactions among alcohol consumption, cigarette smoking, and aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ratios on esophageal cancer. MATERIALS AND METHODS: Alcohol and the risk of incidence and death from esophageal cancer were examined in a 14-year prospective cohort study of 782,632 Korean men, 30 to 93 years of age, who received health insurance from the National Health Insurance Corporation and had a medical evaluation from 1992 to 1995. RESULTS: Smoking, alcohol intake, and AST/ALT ratios were associated with the increased risk of esophageal cancer in a dose-dependent manner independent of each other. Smoking was associated with an increased risk of incidence [Hazard ratio (HR) = 2.2, 95% CI = 1.8 to 2.5] and mortality (HR = 2.5, 2.0 to 3.1). Combined HR of incidence for alcohol consumption (> 25 g/day) and smoking was 4.5 (3.8-5.5); for alcohol (> 25 g/day) and the AST/ALT ratio (> or = 2.0), it was 5.8 (4.6-7.2); for smoking and the AST/ALT ratio (> or = 2.0), it was 6.3 (5.1-7.5). Similar results were seen for mortality from esophageal cancer. Subjects who drank > or = 25 g/day with an AST/ALT ratio > or = 2 had a higher risk of esophageal cancer incidence (HR = 6.5, 4.8 to 8.7) compared with those who drank > or = 25 g/day with an AST/ALT ratio < 2 (HR = 2.2, 1.9 to 2.6). CONCLUSION: Alcohol, smoking, and the AST/ALT ratio are independently associated with increased risk of esophageal cancer but did not interact synergistically. The combination of the AST/ALT ratio with a questionnaire for alcohol consumption may increase the effectiveness for determining the risk of esophageal cancer.

Expressão imuno-histoquímica das metaloproteinases 2 e 9 não está associada à progressão do carcinoma de células escamosas de esôfago / Metalloproteinases 2 and 9 immunohistochemistry expression is not associated to esophageal squamous cell carcinoma progression

INTRODUÇÃO: O carcinoma de células escamosas do esôfago está entre os tipos mais agressivos de câncer e de pior prognóstico. As metaloproteinases de matriz (MMPs), especialmente as MMP-2 e MMP-9, vêm sendo utilizadas para avaliação prognóstica do câncer, associadas a invasão, tamanho e crescimento tumoral. OBJETIVO: O presente estudo visa investigar as expressões imuno-histoquímicas de MMP-2 e MMP-9, avaliando se existe correlação entre sua expressão e o estadiamento tumoral, invasão vascular, invasão local (pT) e diferenciação tumoral no carcinoma de células escamosas de esôfago. MATERIAL E MÉTODO: Foi realizado um estudo retrospectivo utilizando 31 blocos de parafina contendo tumores de carcinoma escamoso esofágico, obtidas por esofagectomias realizadas entre 1998 e 2003, no Hospital Universitário de Santa Maria (HUSM). Os cortes histológicos foram submetidos à reação imuno-histoquímica, com sistema de amplificação por polímero não-biotinilado Novolink para detecção de MMP-2 e MMP-9. RESULTADOS: A avaliação da MMP-2 apresentou positividade fraca em apenas cinco casos, não demonstrando correlação com as variáveis estudadas. Também não foram observadas associações significativas entre as variáveis do estudo e o grau de expressão imuno-histoquímica da MMP-9. CONCLUSÃO: A expressão imuno-histoquímica das MMP-2 e MMP-9 não parece ser influenciada pelos parâmetros investigados. Nesse sentido, estudos adicionais são necessários para melhor compreensão de sua associação aos fatores prognósticos do carcinoma de células escamosas de esôfago.

INTRODUCTION: Esophageal squamous cell carcinoma is an aggressive malignant neoplasia with poor prognosis. The expression of matrix metalloproteinases (MMPs), mainly 2 and 9, has been used for the prognostic evaluation of cancer in association with tumor invasion, size and tumoral growth analysis. OBJECTIVE: The aim of the present study was to investigate the immunohistochemical expression of MMP-2 and MMP-9 and evaluate if there is an association between their expression and tumor staging, vascular invasion, local invasion (pT) and tumoral differentiation in esophageal squamous cell carcinoma. MATERIAL AND METHODS: We conducted a retrospective study using 31 paraffin-embedded specimens of esophageal squamous cell carcinoma obtained by esophagectomies performed at Santa Maria University Hospital, Rio Grande do Sul State, Brazil between 1998 and 2003. The histological sections were immunohistochemically studied using a non-biotinylated Novolink system for MMP-2 and MMP-9 detection. RESULTS: MMP-2 immunohistochemical expression was detected only in 5 cases and did not demonstrate correlation with the variables analyzed. Furthermore, MMP-9 immunohistochemical expression was not significantly associated with the other variables. CONCLUSION: MMP-2 and MMP-9 immunohistochemical expression does not seem to be influenced by the variables reported in this study. Thus further investigations are required to a better understanding of their association with the prognostic factors of esophageal squamous cell carcinoma.

O papel das enzimas CYP2A na susceptibilidade ao câncer do esôfago e sua regulação / The role of CYP2A enzymes in susceptibility to esophageal cancer and its regulation

As nitrosaminas são pré-carcinógenos presentes no cigarro e em alguns alimentos e são os únicos compostos capazes de induzir tumores no esôfago de animais experimentais. Uma vez que as nitrosaminas somente se tornam cancerígenos após serem metabolizadas por enzimas CYP, a presença de um CYP capaz de ativá-las é fundamental para a susceptibilidade tecidual à indução de tumores por estes carcinógenos. A indução de tumores esofágicos pelas nitrosaminas varia entre os animais experimentais, sendo o rato a espécie mais susceptível. Em 2001, nosso grupo identificou o CYP2A3 como sendo a principal enzima responsável pela ativação da NDEA no esôfago de ratos. Por outro lado, nenhuma das nitrosaminas testadas até o momento induz tumores esofágicos no hamster, sendo o fígado o principal órgão-alvo. Com o objetivo de achar uma explicação mecanística para a resistência do esôfago do hamster às nitrosaminas, neste trabalho nós caracterizamos a expressão de enzima CYP2A no esôfago deste animal e comparamos o metabolismo da NDEA entre esôfago e fígado. Mostramos que tanto o esôfago quanto o fígado expressam os mRNAs dos CYP2A8, CYP2A9 e CYP2A16. A expressão protéica, no entanto, é diferente entre os tecidos. Os resultados de Western blotting mostram que, apesar do esôfago e fígado expressarem uma isoforma em comum, o esôfago expressa uma segunda isoforma que não é presente no fígado, enquanto o fígado expressa uma proteína que não é detectada no esôfago. Surpreendentemente, também detectamos uma alta ativação da NDEA pelos microssomos esofágicos. Porém, a eficiência catalítica desta reação foi cerca de 40 vezes menor do que a detectada nos microssomos hepáticos. Um anticorpo anti-CYP2A6 humano foi capaz de inibir o metabolismo da NDEA em microssomos esofágicos, mas não hepáticos. A diferença na eficiência catalítica da reação de NDEA entre esôfago e fígado pode explicar porque as nitrosaminas nunca induzem tumores esofágicos em hamsters. Devido ao papel dos CYP2A...

Nitrosamines are pre-carcinogens found in food and cigarette smoke and are the only compounds known to induce esophageal tumors in experimental animals. Nitrosamines become active carcinogens tumors only after being metabolized by CYP enzymes. Therefore, CYP expression is essential for tissue-specific tumor induction by nitrosamines. Esophageal tumor induction by nitrosamines varies amongst experimental animals, with the rat being the most sensitive species. We have previously shown that CYP2A3 is expressed in the rat esophagus and that CYP2A3 is responsible for NDEA activation in this tissue. On the other hand, none of the nitrosamines tested so far induces esophageal tumors in hamsters, with the liver being the main target-organ for nitrosamine induced tumors. In order to find a mechanistic explanation for its esophageal resistance to nitrosamines, we have characterized CYP2A expression in hamster esophagus and liver and compared NDEA metabolism between these tissues. Hamster esophagus and liver express CYP2A8, CYP2A9 and CYP2A16 mRNAs. However, protein expression is different between the tissues, and our Western blotting results showed that, whereas both the esophagus and liver express two CYP2A isoforms each, only one of the isoforms is similar in both tissues. Surprisingly, we have detected a high NDEA activation in the esophageal microsomes. However, the catalytic efficiency for this reaction was about 40-fold lower than the one detected for hepatic microsomes. An antibody against human CYP26 was able to inhibit NDEA in hamster esophageal, but not liver microsomes. The difference in the catalytic efficiency towards NDEA metabolism between esophagus and liver could help to explain hamster esophageal resistance to nitrosamines. CYP2A inhibition could be a promising approach in chemoprevention, leading to a reduction of the diseases associated with tobacco smoking. There are few data about CYP2A inhibition in experimental animals...

A benzilomino-oxidade (BZAO)-oxidade em portadores de carcinoma esofágico avançado / A Benzylamine-oxidade in patients with advanced esophageal carcinoma

RAcional - A benzilamino-oxidase (BzAO) é uma enzima de substrato fisiológico ainda não totalmente conhecido, presente em todos os tecidos humanos e localiza-se nas células nusculares lisas dos vasos sanguíneos, especulando-se daí que a sua função esteja relacionada a angiogenese...