Disabled-2 inactivation is an early step in ovarian tumorigenicity
Disabled-2 inactivation is an early step in ovarian tumorigenicity
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DOI：
10.1038/sj.onc.1202649
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发表时间：
1999-05-20
期刊：
影响因子：
8
通讯作者：
Xu, XX
中科院分区：
文献类型：
--
作者：
Fazili, Z;Sun, WP;Xu, XX
DISABLED-2(DAB2)在有丝分裂信号转导通路中发挥作用，在肿瘤中经常被纯合子基因缺失激活，提示DAB2是一种候选的肿瘤抑制因子。在这里，我们调查了DAB2的表达情况，报道了DAB2在各种组织中的表达，并且在卵巢和乳腺中的表达水平特别高。在永生化的乳腺和卵巢上皮细胞中也检测到DAB2的表达。然而，在用Western blotting检测的来自乳腺和卵巢上皮性肿瘤的十几个已建立的肿瘤细胞系中，90%的这些细胞系没有检测到DAB2的表达。用特异性抗DAB2抗体对人卵巢组织进行组织学染色，发现DAB2在卵巢表面上皮层高表达。在26例卵巢癌的免疫组织学研究中，发现22例(85%)的卵巢癌上皮源性肿瘤细胞中DAB2表达缺失。DAB2的表达缺失与肿瘤分级无关，提示DAB2在肿瘤发生的早期就已丢失。事实上，DAB2的丢失与表面上皮细胞的形态转化密切相关。此外，DAB2蛋白的丢失发生在高增殖但组织学上的良性卵巢上皮，提示DAB2的丢失发生在癌前病变中。因此，本研究表明DAB2的表达缺失与细胞的致瘤性有关，而与肿瘤的级别无关，并且DAB2的表达缺失是卵巢恶性肿瘤的早期事件。
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 premalignant 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.