Frequent downregulation and loss of WWOX gene expression in human hepatocellular carcinoma.
Frequent downregulation and loss of WWOX gene expression in human hepatocellular carcinoma.
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DOI：
10.1038/sj.bjc.6602023
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发表时间：
2004-08-16
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
WWOX(WW结构域包含氧化还原酶)是一种候选的肿瘤抑制基因，与第二常见的脆性位点FRA16D位于同一染色体区域16q23。比较基因组杂交(CGH)检测到染色体16Q上微卫星标记的缺失和杂合性丢失在包括肝细胞癌(HCC)在内的许多人类癌症中很常见。人类肝细胞癌的发展与接触致癌病毒和化学致癌物密切相关，已知这些物质经常以常见的FS为靶点。我们检测了18个来自人肝癌细胞系的WWOX基因组DNA、RNA和蛋白质的状态，发现该基因反复发生变化。CGH检测到多个细胞系16q23条带DNA拷贝数丢失。虽然没有检测到WWOX基因的纯合缺失，但在60%的细胞系中WWOX mRNA表达缺失或降低。WWOX外显子6-8缺失的反转录-聚合酶链式反应产物异常的发生与WWOX表达的改变显著相关。用WWOX抗体进行Western blotting检测，所有表达下调的细胞系的WWOX蛋白水平均降低或检测不到。此外，与正常肝脏相比，18个细胞系中有13个细胞株表达水平降低或没有WWOX蛋白。这些结果表明，WWOX基因在肝细胞癌中经常发生改变，这增加了该基因参与肝癌发生的可能性。
The WWOX (WW-domain containing oxidoreductase) is a candidate tumour suppressor gene spanning the same chromosome region, 16q23, as the second most common fragile site (FS), FRA16D. Deletions detected by comparative genomic hybridisation (CGH) and loss of heterozygosity at microsatellite markers on chromosome 16q are common in many human cancers including hepatocellular carcinoma (HCC). The development of human HCC is closely associated with exposure to oncogenic viruses and chemical carcinogens, agents known to frequently target common FS. We examined the status of WWOX genomic DNA, RNA and protein in 18 cell lines derived from human HCC and found recurrent alterations of the gene. Loss of DNA copy-number confined to band 16q23 was detected by CGH in several cell lines. Although homozygous deletions of the WWOX gene were not detected, WWOX mRNA expression was absent or lower in 60% of cell lines. The occurrence of aberrant WWOX reverse transcription–PCR products with deletion of exons 6–8 correlated significantly with altered WWOX expression. All of the cell lines showing mRNA downregulation had a decreased or undetectable level of WWOX protein as demonstrated by Western blotting with antibody to WWOX. Furthermore, 13 out of the 18 cell lines expressed decreased levels or no WWOX protein when compared with normal liver. These results show that WWOX gene is frequently altered in HCC and raise the possibility that this gene is implicated in hepatocarcinogenesis.
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