Expressão de proteinas envolvidas na etiopatogenia do linfoma gástrico Malt / Protein expression involved in the etiopathogenesis of gastric MALT lymphoma

RESUMO

INTRODUÇÃO: O linfoma gástrico do tecido linfóide associado à mucosa (MALT) representa o tipo mais freqüente de linfoma MALT e é associado à infecção crônica pelo Helicobacter pylori. ... A diversidade da manifestação clínica é determina por fatores do hospedeiro e da bactéria cuja interação determina padrões distintos de resposta. OBJETIVO: Determinar o padrão de expressão de proteínas envolvidas na via extrínseca de apoptose, na resposta imune e inflamatória e na via de sinalização NF-κB do linfoma gástrico MALT e compará-lo com o padrão encontrado nas gastrites e no estômago normal. MATERIAL e MÉTODOS: Descrevemos a expressão de proteínas envolvidas nas vias de apoptose (FAS, FAS-L,Caspase 8 e Granzima B), na resposta imunológica e inflamatória (HLA-DR, STAT-1, S-100 e NOS-2) e das proteínas que participam da via de ativação do NF-κB (Bcl-10 e c-rel), do linfoma gástrico MALT, avaliadas por imunoistoquímica. ... RESULTADOS: Observamos diminuição da expressão do FAS-L e do FAS no tumor, quando comparados à gastrite (p<0,001, p<0,001 respectivamente) e ao tecido normal (p<0,001, p<0,001 respectivamente). ...... CONCLUSÃO: No linfoma MALT o padrão de expressão das proteínas estudadas difere dos grupos controle. Nossos resultados sugerem comprometimento da via extrínseca de apoptose nos linfomas MALT devido à reduzida expressão de FAS-FAS-L e ausência de sinais de ativação da caspase-8. As proteínas envolvidas na apresentação de antígenos estão muito expressas no MALT, (HLA-DR, STAT-1 e S-100), o que pode ser conseqüência da estimulação antigênica e determinante da proliferação de células B. Encontramos intensa expressão do c-Rel nos linfomas MALT, o que pode significar que esta subunidade do NF-κB participe da gênese do processo neoplásico, seja por indução da proliferação, seja por estar envolvida na gênese de inibidores da apoptose.

ABSTRACT

Introduction: The gastric lymphoma of the mucosal associated lymphoid tissue (MALT) represents the most frequent MALT lymphoma and is associated with chronic Helicobacter Pylori infection. The gastric mucosal infection by Helicobacter pylori occurs in more than half of the world population, thus leading to a broad spectrum of clinical presentations including symptomatic gastritis, peptic ulcer, gastric carcinoma, and MALT lymphoma. The diverse clinical manifestations are determined by host factors and bacterial interactions leading to different types of responses. Objective: To determine the pattern of protein expression involved in the extrinsic apoptotic pathway, in the immune and inflammatory responses, and in the signaling pathway of NF-κB of the Gastric MALT Lymphoma and to compare it with the standard pattern found in gastritis and the normal stomach. Material and methods: We described the expression of proteins involved in the apoptotic pathways (FAS, FAS-L, Caspase 8 and Granzime B), in the immune and inflammatory responses (HLA-DR, STAT-1, S-100 and NOS-2), as well as the proteins that participate in the activation of NF- κB (Bcl-10 and c-Rel), in the MALT Gastric Lymphoma via Immunohistochemistry. We analyzed 56 biopsy specimens of gastric MALT lymphoma, 28 biopsy specimens of gastritis, and 35 normal gastric tissues. The Kruskal Wallis non parametric test was used to compare the intensity of marker expression amongst the three groups (α=.05). For the multiple comparisons, the MannWhitney test was used with the Bonferroni correction for alpha error (α= .0167). Results: We observed a decrease in the expression FAS-L and FAS in the tumor when compared to gastritis and normal mucosa (p<0,001, p<0,001 respectively). The lymphoma has areas that are clearly negative for FAS. The expression of Caspase-8 was more frequent in gastritis than in MALT lymphoma and in normal tissue (p=0,006, p=0,04 respectively). The presence of Granzime B in the MALT lymphoma was more frequent with statistic significance when compared with normal tissue (p<0,001) and gastritis (p=0,014). The expression of the HLA-DR, STAT-1, S-100 was more frequent in the tumor than the normal mucosa (p<0,001, p<0,001, p<0,001 respectively) and gastritis (p<0,001, p<0,01, p<0,001 respectively). The presence of NOS-2 expression was less frequent in the group with MALT lymphoma and the difference between gastritis and normal mucosa was statistically significant (p<0,001 and p=0,001). c-Rel expression was higher in MALT lymphoma compared to normal tissue (p<0,001) and gastritis (p<0,001). The predominantly nuclear and intense expression of Bcl-10 was only observed in the tumor in 11 of the 54 specimens that were analyzed. CONCLUSION: In the MALT lymphoma, the patterns of protein expression differ from the control groups. Our results suggest a compromised extrinsic apoptotic pathway in the MALT lymphomas due to a reduced expression of the FAS-FAS-L and the absence of activation signals of caspase-8. The proteins involved in antigen presentation (HLA-DR, STAT-1 and S-100) are highly expressed in MALT lymphoma, which may be a consequence of antigenic stimulation and may be responsible for B cell proliferation. We found intense expression of c-Rel in the MALT lymphomas, suggesting that this NF-Kß subunit participates in the initiation of the neoplastic process, either through induction of proliferation or through the synthesis of inhibitors of apoptosis.