Fazili Z, Sun W, Mittelstaedt S, Cohen C, Xu X X
Department of Biochemistry and Winship Cancer Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Oncogene. 1999 May 20;18(20):3104-13. doi: 10.1038/sj.onc.1202649.
Disabled-2 (Dab2) functions in mitogenic signal transduction pathway, and is frequently activated by homozygous gene deletion in tumors, suggesting that Dab2 is a candidate tumor suppressor. Here, we surveyed the expression of Dab2, and report that Dab2 is expressed in a variety of tissues, and the level of expression is particularly high in ovary and breast. Dab2 expression was also detected in immortalized breast and ovarian epithelial cells. However, in more than a dozen established tumor cell lines derived from breast and ovarian epithelial tumors examined by Western blotting, Dab2 expression was undetectable in 90% of these cell lines. Histological staining of human ovarian tissues with specific anti-Dab2 antibodies indicated that Dab2 is highly expressed in the surface epithelial layer. In an immunohistological study of 26 ovarian carcinomas, 22 (85%) of the tumors were found to lose the expression of Dab2 in the tumor cells, which are epithelial origin. Loss of Dab2 expression is not correlated with tumor grade, suggesting that Dab2 is lost in an early stage of tumorigenicity. Indeed, loss of Dab2 correlates closely with morphological transformation of the surface epithelial cells. Additionally, loss of Dab2 protein occurs in hyperproliferative, but histological benign ovarian epithelium, suggesting that loss of Dab2 occurs in pre-malignant lesions. Thus, this study indicates that the loss of Dab2 expression is correlated with tumorigenicity of the cells disregarding the grade of the tumors, and loss of Dab2 expression is an early event in ovarian malignancies.
Disabled-2（Dab2）在有丝分裂原信号转导途径中发挥作用，且在肿瘤中常因纯合基因缺失而被激活，这表明Dab2是一种候选肿瘤抑制因子。在此，我们检测了Dab2的表达情况，并报告Dab2在多种组织中均有表达，其中在卵巢和乳腺中的表达水平尤其高。在永生化的乳腺和卵巢上皮细胞中也检测到了Dab2的表达。然而，在通过蛋白质印迹法检测的十几种源自乳腺和卵巢上皮肿瘤的已建立肿瘤细胞系中，90%的细胞系未检测到Dab2的表达。用人卵巢组织特异性抗Dab2抗体进行组织学染色表明，Dab2在表面上皮层中高表达。在一项对26例卵巢癌的免疫组织学研究中，发现其中22例（85%）肿瘤细胞（起源于上皮）中Dab2表达缺失。Dab2表达缺失与肿瘤分级无关，这表明Dab2在肿瘤发生的早期阶段就已缺失。实际上，Dab2的缺失与表面上皮细胞的形态转化密切相关。此外，在增殖过度但组织学上为良性的卵巢上皮中也出现了Dab2蛋白缺失的情况，这表明Dab2的缺失发生在癌前病变中。因此，本研究表明，无论肿瘤分级如何，Dab2表达缺失均与细胞的肿瘤发生相关联，且Dab2表达缺失是卵巢恶性肿瘤中的一个早期事件。
