Homozygous deletion of MKK4 in ovarian serous carcinoma
Homozygous deletion of MKK4 in ovarian serous carcinoma
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DOI：
10.4161/cbt.5.6.2675
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发表时间：
2006-06-01
影响因子：
3.6
通讯作者：
Wang, Tian-Li
中科院分区：
文献类型：
--
作者：
Nakayama, Kentaro;Nakayama, Naomi;Wang, Tian-Li
在肿瘤中缺失的染色体区域的分析在历史上导致了肿瘤抑制基因的鉴定。在这项研究中，我们使用数字核型分析，一个全基因组，高分辨率的技术，以寻找染色体缺失的卵巢浆液性癌，最致命的妇科恶性肿瘤的妇女。五个纯化的卵巢浆液性癌进行了分析，通过数字核型分析和小间质缺失染色体17 p在两个肿瘤样本中被确定。比对这两个缺失鉴定了跨越2.4 Mb的重叠区域，其含有候选肿瘤抑制基因，丝裂原活化蛋白激酶激酶-4（MKK 4）。双色荧光原位杂交分析证实了两个样本中MKK 4基因座的纯合性缺失，RT-PCR表明两种癌都缺乏MKK 4转录本表达。28例高级别浆液性癌中有24例（86%）发生17 p杂合性缺失，包括两例纯合性MKK 4缺失。此外，与良性卵巢组织相比，在128例卵巢浆液性癌中有96例（75%）发现MKK 4表达下调。这些结果表明，MKK 4的纯合性缺失或表达减少可能有助于卵巢浆液性癌的发展。
Analysis of deleted chromosomal regions in tumors has historically led to the identification of tumor suppressor genes. In this study, we used digital karyotyping, a genome-wide, high-resolution technology, to search for chromosomal deletions in ovarian serous carcinoma, the most lethal gynecological malignancy in women. Five purified ovarian serous carcinomas were analyzed by digital karyotyping and small interstitial deletions at chromosome 17p were identified in two tumor samples. Aligning these two deletions identified an overlapping region that spanned 2.4 Mb which harbored a candidate tumor suppressor gene, mitogen-activated protein kinase kinase-4 (MKK4). Dual-color FISH analysis confirmed homozygous deletion of the MKK4 locus in both samples and RT-PCR demonstrated that both carcinomas lacked MKK4 transcript expression. Loss of heterozygosity of 17p occurred in 24 (86%) of 28 high-grade serous carcinomas including both cases with homozygous MKK4 deletion. Additionally, downregulation of MKK4 expression was found in 96 (75%) of 128 ovarian serous carcinomas as compared to benign ovarian tissues. These findings suggest that homozygous deletion or reduced expression of MKK4 may contribute to the development of ovarian serous carcinoma.