Altered expression of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in transformed non-lymphoid human tissues
Altered expression of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in transformed non-lymphoid human tissues
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DOI：
10.1002/jcp.21454
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发表时间：
2008-09-01
影响因子：
5.6
通讯作者：
Natai, Pier Giorgio
中科院分区：
文献类型：
--
作者：
Fruci, Doriana;Giacomini, Patrizio;Natai, Pier Giorgio
内质网（ER）氨基肽酶ERAP 1和ERAP 2有助于产生HLA I类结合肽。最近，我们已经表明，这些酶的表达是高的和协调的（彼此和与HLA I类分子）在永生化B细胞，但可变的和不平衡的各种非淋巴谱系的人肿瘤细胞系。在此，通过测试ERAP 1和ERAP 2在正常非淋巴组织及其恶性对应物中的表达来研究该问题。ERAP 1和ERAP 2仅在超过一半的测试正常组织的上皮细胞中检测到。检测到4种ERAP 1/ERAP 2表型（+/+、-/-、+/-和-/+），并且任一种或两种酶的存在不一定与HLA 1类表达相关。在超过160个肿瘤病变中，根据肿瘤组织型，与正常对应物相比，一种或两种氨基肽酶的表达被保留、丢失（最常见，特别是ERAP 1）或获得。双阴性（-/-）表型是最常见的，并显着（P=0.013）与缺乏可检测的HLA 1类抗原。在选定的肿瘤病变中，还测试了ERAP 1和ERAP 2的酶（肽修剪）活性。发现表达和功能相关，表明免疫组织化学检测体内活性酶。因此，ERAP 1、ERAP 2和HLA 1类表达的解离可能已经存在于一些正常组织中，但恶性转化导致特定肿瘤组织型的额外损失、增益和不平衡，并且这些改变了体内肿瘤细胞的肽修剪能力。
The encloplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 contribute to generate HLA class I binding peptides. Recently, we have shown that the expression of these enzymes is high and coordinated (with each other and with HLA class I molecules) in immortalized B cells, but variable and imbalanced inhuman tumour cell lines of various non-lymphoid lineages. Herein, this issue was investigated in vivo by testing ERAP1 and ERAP2 expression in normal non-lymphoid tissues and their malignant counterparts. ERAP1 and ERAP2 were detected exclusively in the epithelial cells of over half of the tested normal tissues. Four ERAP1/ERAP2 phenotypes (+/+, -/-, +/- and -/+) were detected, and the presence of either or both enzymes was not necessarily associated with HLA class 1 expression. In more than 160 neoplastic lesions, the expression of either or both aminopeptidases was retained, lost (most frequently, particularly ERAP1) or acquired as compared to the normal counterparts, depending on the tumour histotype. The double-negative (-/-) phenotype was the most frequent, and significantly (P=0.013) associated with a lack of detectable HLA class 1 antigens. In selected neoplastic lesions, ERAP1 and ERAP2 were also tested for their enzymatic (peptide-trimming) activities. Expression and function were found to correlate, indicating that immunohistochemistry detects active enzymes in vivo. Thus, dissociation in the expression of ERAP1, ERAP2 and HLA class 1 may already be present in some normal tissues, but malignant transformation causes additional losses, gains and imbalances in specific tumour histotypes, and these alter the peptide-trimming ability of tumour cells in vivo.