Wwox hypomorphic mice display a higher incidence of B-Cell lymphomas and develop testicular atrophy
Wwox hypomorphic mice display a higher incidence of B-Cell lymphomas and develop testicular atrophy
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DOI：
10.1002/gcc.20497
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发表时间：
2007-12-01
影响因子：
3.7
通讯作者：
Aldaz, C. Marcelo
中科院分区：
文献类型：
--
作者：
Ludes-Meyers, John H.;Kil, Hyunsuk;Aldaz, C. Marcelo
WWOX是一个假定的肿瘤抑制基因，编码在染色体16 q23带中的常见染色体脆性位点区域FRA 16 D内。多项研究表明，WWOX表达在各种肿瘤类型中通常减少或丢失。通过在乳腺、卵巢和肺肿瘤细胞系中重新表达WWOX，导致体内肿瘤生长抑制，提示了WWOX肿瘤抑制活性。为了确定Wwox基因表达的缺失是否在肿瘤发生中起作用，我们产生了含有通过基因捕获载体突变的Wwox基因的小鼠品系。纯合子Wwoxgene-trap小鼠（Wwox（gt/gt））在检查的大多数组织中没有检测到Wwox蛋白，尽管在少数组织中可以检测到低水平。由于这些观察结果，我们得出结论，这些小鼠是Wwox亚型。值得注意的是，与最近报道的Wwox基因敲除小鼠的出生后致死率相比，Wwox亚型小鼠是可行的。与野生型对应物相比，来自Wwox（gt/gt）雄性的睾丸具有大量萎缩的生精小管和降低的生育力。我们观察到Wwox（gt/gt）小鼠的寿命明显较短，雌性亚型小鼠自发性B细胞淋巴瘤的发病率较高。总之，我们描述了一种新的Wwox亚型小鼠模型，克服了出生后的致命性，最近观察到的Wwox基因敲除小鼠。因此，使用该模型的肿瘤发生研究更接近地概括了在人类癌症中观察到的WWOX表达的丧失。重要的是，我们观察到Wwox亚型B细胞淋巴瘤的发病率增加，这支持了Wwox作为肿瘤抑制因子的作用。
WWOX is a putative tumor suppressor gene encoded within common chromosomal fragile site region FRA 16D, in chromosome band 16q23. Multiple studies have demonstrated that WWOX expression is often reduced or lost in various tumor types. WWOX tumor suppressor activity was suggested by re-expressing WWOX in breast, ovarian, and lung tumor cell lines leading to tumor growth inhibition in vivo. To determine whether loss of Wwox gene expression has a role in tumorigenesis, we generated a mouse strain containing a Wwoxgene mutated by a gene-trap vector. Homozygous Wwoxgene-trap mice (Wwox(gt/gt)) had no detectable Wwox protein in most tissues examined, although, a low level could be detected in a minority of tissues. Because of these observations, we concluded that these mice are Wwox hypomorphs. Remarkably, Wwox hypomorphic mice are viable in contrast to the recently reported postnatal lethality of Wwox knockout mice. Testes from Wwox(gt/gt) males had high numbers of atrophic seminiferous tubules and reduced fertility when compared with wild-type counterparts. We observed that the Wwox(gt/gt) mice had a significantly shorter lifespan, and female hypomorphs had a higher incidence of spontaneous B-cell lymphomas. In conclusion, we describe a novel Wwox hypomorphic mouse model that overcomes postnatal lethality that was recently observed in Wwox knockout mice. Therefore, tumorigenesis studies using this model more closely recapitulates the loss of WWOX expression observed in human cancers. Importantly, our observation that Wwox hypomorphs had an increased incidence of B-cell lymphomas supports a role of Wwox as a tumor suppressor.