Brooks D J, Woodward S, Thompson F H, Dos Santos B, Russell M, Yang J M, Guan X Y, Trent J, Alberts D S, Taetle R
Department of Medicine, University of Arizona and Arizona Cancer Center, Tucson 85724, USA.
Br J Cancer. 1996 Nov;74(10):1518-25. doi: 10.1038/bjc.1996.583.
The EVI-1 gene was originally detected as an ectopic viral insertion site and encodes a nuclear zinc finger DNA-binding protein. Previous studies showed restricted EVI-1 RNA or protein expression during ontogeny; in a kidney and an endometrial carcinoma cell line; and in normal murine oocytes and kidney cells. EVI-1 expression was also detected in a subset of acute myeloid leukaemias (AMLs) and myelodysplasia. Because EVI-1 is expressed in the urogenital tract during development, we examined ovarian cancers and normal ovaries for EVI-1 RNA expression using reverse transcription polymerase chain reaction (RT-PCR) and RNAase protection. Chromosome abnormalities were examined using karyotypes and whole chromosome 3 and 3q26 fluorescence in situ hybridisation (FISH). RNA from six primary ovarian tumours, five normal ovaries and 47 tumour cell lines (25 ovarian, seven melanoma, three prostate, seven breast and one each of bladder, endometrial, lung, epidermoid and histiocytic lymphoma) was studied. Five of six primary ovarian tumours, three of five normal ovaries and 22 of 25 ovarian cell lines expressed EVI-1 RNA. A variety of other non-haematological cancers also expressed EVI-1 RNA. Immunostaining of ovarian cancer cell lines revealed nuclear EVI-1 protein. In contrast, normal ovary stained primarily within oocytes and faintly in stroma. Primary ovarian tumours showed nuclear and intense, diffuse cytoplasmic staining. Quantitation of EVI-1 RNA, performed using RNAase protection, showed ovarian carcinoma cells expressed 0 to 40 times the EVI-1 RNA in normal ovary, and 0-6 times the levels in leukaemia cell lines. Southern analyses of ovarian carcinoma cell lines showed no amplification or rearrangements involving EVI-1. In some acute leukaemias, activation of EVI-1 transcription is associated with translocations involving 3q26, the site of the EVI-1 gene. Ovarian carcinoma karyotypes showed one line with quadruplication 3(q24q27), but no other clonal structural rearrangements involving 3q26. However, whole chromsome 3 and 3q26 FISH performed on lines with high EVI-1 expression showed translocations involving chromosome 3q26. EVI-1 is overexpressed in ovarian cancer compared with normal ovaries, suggesting a role for EVI-1 in solid tumour carcinogenesis or progression. Mechanisms underlying EVI-1 overexpression remain unclear, but may include rearrangements involving chromosome 3q26.
EVI-1基因最初作为一个异位病毒插入位点被检测到，它编码一种核锌指DNA结合蛋白。先前的研究表明，EVI-1 RNA或蛋白在个体发育过程中、在一个肾和一个子宫内膜癌细胞系中、以及在正常小鼠卵母细胞和肾细胞中表达受限。在一部分急性髓系白血病（AML）和骨髓发育异常中也检测到了EVI-1的表达。由于EVI-1在发育过程中于泌尿生殖道表达，我们使用逆转录聚合酶链反应（RT-PCR）和RNA酶保护法检测了卵巢癌组织和正常卵巢组织中的EVI-1 RNA表达。使用核型分析以及全染色体3和3q26荧光原位杂交（FISH）检测染色体异常情况。研究了来自6例原发性卵巢肿瘤、5例正常卵巢以及47个肿瘤细胞系（25个卵巢癌、7个黑色素瘤、3个前列腺癌、7个乳腺癌以及1个膀胱癌、子宫内膜癌、肺癌、表皮样癌和组织细胞淋巴瘤细胞系）的RNA。6例原发性卵巢肿瘤中的5例、5例正常卵巢中的3例以及25个卵巢癌细胞系中的22个表达EVI-1 RNA。多种其他非血液系统癌症也表达EVI-1 RNA。卵巢癌细胞系的免疫染色显示有核EVI-1蛋白。相比之下，正常卵巢主要在卵母细胞中染色，在基质中染色较淡。原发性卵巢肿瘤显示有核染色以及强烈的弥漫性细胞质染色。使用RNA酶保护法对EVI-1 RNA进行定量分析显示，卵巢癌细胞表达的EVI-1 RNA是正常卵巢中的0至40倍，是白血病细胞系中水平的0至6倍。对卵巢癌细胞系进行的Southern分析显示没有涉及EVI-1的扩增或重排。在一些急性白血病中，EVI-1转录的激活与涉及3q26（EVI-1基因所在位点）的易位有关。卵巢癌核型分析显示有一个细胞系存在3号染色体（q24q27）四倍体，但没有其他涉及3q26的克隆性结构重排。然而，对EVI-1高表达的细胞系进行全染色体3和3q26 FISH检测显示存在涉及染色体3q26的易位。与正常卵巢相比，EVI-1在卵巢癌中过表达，提示EVI-1在实体肿瘤的发生或进展中起作用。EVI-1过表达的潜在机制尚不清楚，但可能包括涉及染色体3q26的重排。
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