The amplified WWP1 gene is a potential molecular target in breast cancer
The amplified WWP1 gene is a potential molecular target in breast cancer
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DOI：
10.1002/ijc.22653
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发表时间：
2007-07-01
影响因子：
6.4
通讯作者：
Dong, Jin-Tang
中科院分区：
文献类型：
--
作者：
Chen, Ceshi;Zhou, Zhongmei;Dong, Jin-Tang
8号染色体的q21带(8q21)的扩增出现在很大比例的乳腺癌中。WWP1是一种含有Hect结构域的泛素E3连接酶，位于8q21区域，负向调节转化生长因子-β肿瘤抑制通路。为了研究WWP1在乳腺癌中的作用，我们分析了WWP1基因的剂量、表达水平以及WWP1的S功能。在51%(18/35)的乳腺癌细胞系和41%(17/41)的乳腺原发肿瘤中，WWP1基因的拷贝数增加。用实时荧光定量RT-PCR、Northern印迹和Western印迹分析WWP1mRNA、NAS的表达。WWP1mRNA在58%(19/33)的乳腺癌细胞系中表达上调，并且WWP1的过度表达与基因拷贝数的增加显著相关。在一组来自乳腺原发肿瘤和正常组织的cDNA中，WWP1在肿瘤中的表达显著高于正常组织。在功能上，RNAi介导的WWP1基因敲除显著诱导了MCF7和HCC1500乳腺癌细胞株的生长停滞和凋亡。一致地，WWP1抑制激活了caspase。慢病毒系统强迫WWP1在2个永生化乳腺上皮细胞系MCF10A和184B5中过表达可促进细胞增殖。这些结果提示，WWP1的基因组异常可能参与了乳腺癌的发病机制。(C)2007年Wiley-Liss，Inc.
The amplification of the q21 band of chromosome 8 (8q21) occurs in a large percentage of breast cancers. WWP1, an HECT domain-containing ubiquitin E3 ligase located in the 8q21 region, negatively regulates the TGF-beta tumor suppressor pathway. To characterize the role of WWP1 in breast cancer, we analyzed WWP1 gene dosage and expression level as well as WWP1's function. A copy number gain of WWP1 was found in 51% (18/35) of breast cancer cell lines and in 41% (17/41) of primary breast tumors. Expression of WWP1 mRNA,Nas analyzed with real-time RT-PCR, Northern blot, and Western blot. WWP1 mRNA is upregulated in 58% (19/33) of breast cancer cell lines, and overexpression of WWP1 is significantly correlated with a gene copy number gain. In a panel of cDNA from primary breast tumors and normal tissues, expression of WWP1 in tumors is significantly higher than that in normal tissues. Functionally, RNAi-mediated WWP1 knockdown significantly induced cell growth arrest and apoptosis in the MCF7 and HCC1500 breast cancer cell lines. Consistently, WWP1 inhibition activated caspases. Forced over-expression of WWP1 by the lentiviral system in 2 immortalized breast epithelial cell lines MCF10A and 184B5 promoted cell proliferation. These results suggest that genomic aberrations of WWP1 may contribute to the pathogenesis of breast cancer. (C) 2007 Wiley-Liss, Inc.