WWOX, the FRA16D gene, behaves as a suppressor of tumor growth.
WWOX, the FRA16D gene, behaves as a suppressor of tumor growth.
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发表时间：
2001-11
期刊：
影响因子：
11.2
通讯作者：
A. Bednarek;C. Keck-Waggoner;R. Daniel;K. J. Laflin;P. Bergsagel;K. Kiguchi;A. Brenner;Claudio Marcelo Aldaz
中科院分区：
文献类型：
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作者：
A. Bednarek;C. Keck-Waggoner;R. Daniel;K. J. Laflin;P. Bergsagel;K. Kiguchi;A. Brenner;Claudio Marcelo Aldaz
我们最近报道了WWOX基因的克隆，该基因定位于染色体16q23.3-24.1的共同脆性位点FRA 16 D区域。观察到WWOX跨越的基因组区域受到染色体易位和纯合缺失的影响。此外，在乳腺癌、卵巢癌、前列腺癌和影响该区域的其他癌症中等位基因丢失的高发生率表明WWOX是候选的肿瘤抑制基因。WWOX的表达在乳腺癌细胞系中是高度可变的，在一些情况下显示出低或不可检测的表达水平。在这份报告中，我们证明异位WWOX表达强烈抑制乳腺癌细胞系MDA-MB-435和T47 D在软琼脂中的锚定非依赖性生长。此外，我们观察到WWOX在体内测试时诱导MDA-MB-435乳腺癌细胞的致瘤性的显著抑制。我们还检测到在各种癌细胞系、多发性骨髓瘤细胞系和原发性乳腺肿瘤中常见的具有外显子5-8或6-8缺失的异常WWOX转录物。在正常组织中未检测到这些异常的mRNA形式。有趣的是，我们进一步观察到，由这种异常转录本编码的蛋白质显示异常的核定位，而野生型WWOX蛋白质定位于高尔基体系统。我们的数据表明，WWOX的行为作为一个有效的肿瘤生长抑制剂，并建议在基因组和转录水平上影响该基因的异常可能是相关的致癌作用。
We recently reported the cloning of WWOX, a gene that maps to the common fragile site FRA16D region in chromosome 16q23.3-24.1. It was observed that the genomic area spanned by WWOX is affected by chromosomal translocations and homozygous deletions. Furthermore, the high incidence of allelic loss in breast, ovarian, prostate, and other cancers affecting this region suggests that WWOX is a candidate tumor suppressor gene. Expression of WWOX is highly variable in breast cancer cell lines, with some cases showing low or undetectable levels of expression. In this report, we demonstrate that ectopic WWOX expression strongly inhibits anchorage-independent growth in soft agar of breast cancer cell lines MDA-MB-435 and T47D. Additionally, we observed that WWOX induces a dramatic inhibition of tumorigenicity of MDA-MB-435 breast cancer cells when tested in vivo. We also detected the common occurrence of aberrant WWOX transcripts with deletions of exons 5-8 or 6-8 in various carcinoma cell lines, multiple myeloma cell lines, and primary breast tumors. These aberrant mRNA forms were not detected in normal tissues. Interestingly, we further observed that proteins encoded by such aberrant transcripts display an abnormal nuclear localization in contrast to the wild-type WWOX protein that localizes to the Golgi system. Our data indicate that WWOX behaves as a potent suppressor of tumor growth and suggest that abnormalities affecting this gene at the genomic and transcriptional level may be of relevance in carcinogenesis.