Parenti Anna, Leo Genesio, Porzionato Andrea, Zaninotto Giovanni, Rosato Antonio, Ninfo Vito
Section of Pathologic Anatomy, Department of Oncological and Surgical Sciences, University of Padova, 35100, Italy.
Hum Pathol. 2006 Jan;37(1):16-22. doi: 10.1016/j.humpath.2005.10.003.
The regulation of apoptosis, as a distinctive form of programmed cell death, in multistep Barrett's esophagus (BE) carcinogenesis is poorly understood. The aim of this study was to investigate, in the intestinal metaplasia-dysplasia-carcinoma sequence, the role of survivin, an inhibitor of apoptosis; the p53 protein, a tumor suppressor gene involved in cell cycle control; and caspase 3, a protease-inducing apoptosis and inhibited by survivin. Immunohistochemical expression was tested in 40 cases of BE, including 11 low-grade and 19 high-grade dysplasias (HGD), and samples were obtained from 40 surgical specimens of esophagectomy performed for HGD or Barrett's adenocarcinoma. To define the deregulation time of the proteins, overexpression was evaluated in relation to the proliferative and/or maturative compartment. In BE, cytoplasmic expression of survivin and caspase 3 (100% of cases) was significantly higher than expression of p53 (25%). The latter increased with increasing grade of dysplasia. In BE, the expression of survivin, p53, and caspase 3 mainly involved the proliferative compartment, whereas in LGD and HGD, the 3 proteins were coexpressed in both proliferative and maturative compartments. These results indicate that survivin overexpression is an early event in the proliferative compartment of BE, preceding both p53 accumulation and dysplastic changes. Cytoplasmic survivin location may indicate an initial antiapoptotic, more than proliferative, role in the early phases of Barrett carcinogenesis. Expression of caspase 3 in BE and dysplasia may be ascribed to accumulation of the nonactivated form, as the antibody used detects both cleaved and uncleaved caspase 3.
作为一种独特的程序性细胞死亡形式，细胞凋亡在多步骤的巴雷特食管（BE）癌变过程中的调控机制尚不清楚。本研究旨在探讨凋亡抑制因子survivin、参与细胞周期调控的肿瘤抑制基因p53蛋白以及诱导凋亡且受survivin抑制的蛋白酶caspase 3在肠化生-发育异常-癌序列中的作用。对40例BE进行免疫组化表达检测，其中包括11例低级别和19例高级别发育异常（HGD），样本取自因HGD或巴雷特腺癌而进行食管切除术的40例手术标本。为了确定这些蛋白质的失调时间，根据增殖和/或成熟区室评估其过表达情况。在BE中，survivin和caspase 3的细胞质表达（100%的病例）显著高于p53的表达（25%）。随着发育异常程度的增加，p53表达升高。在BE中，survivin、p53和caspase 3的表达主要涉及增殖区室，而在低级别发育异常（LGD）和高级别发育异常（HGD）中，这三种蛋白质在增殖区室和成熟区室均有共表达。这些结果表明，survivin过表达是BE增殖区室中的早期事件，早于p53积累和发育异常变化。细胞质中survivin的定位可能表明其在巴雷特癌变早期阶段具有初始的抗凋亡作用，而非增殖作用。BE和发育异常中caspase 3的表达可能归因于未激活形式的积累，因为所使用的抗体可检测到裂解和未裂解的caspase 3。
