WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3
WWOX Gene Expression Abolishes Ovarian Cancer Tumorigenicity In vivo and Decreases Attachment to Fibronectin via Integrin α3
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DOI：
10.1158/0008-5472.can-08-2974
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发表时间：
2009-06-01
期刊：
影响因子：
11.2
通讯作者：
Gabra, Hani
中科院分区：
文献类型：
--
作者：
Gourley, Charlie;Paige, Adam J. W.;Gabra, Hani
包含WW结构域的氧化还原酶(WWOX)基因位于FRA16D，这是一种与人类癌症有关的常见脆性部位。在小鼠中靶向缺失WWOX会导致自发肿瘤发生率增加，证实WWOX是一个真正的肿瘤抑制基因。我们发现，稳定地将WWOX基因导入含有WWOX纯合子缺失的人卵巢癌细胞PEO1，可以消除体内的致瘤性，但这与体外生长的变化无关。相反，在PEO1中恢复WWOX，或在SKOV3卵巢癌细胞中过度表达WWOX，会导致纤维连接蛋白的附着和迁移减少，纤维连接蛋白是一种与腹膜转移有关的细胞外基质成分。相反，siRNA介导的内源性WWOX在A2780卵巢癌细胞中的敲除增加了对纤维连接蛋白的黏附。此外，虽然在贴壁细胞中没有依赖WWOX的细胞死亡的差异，但在悬浮培养中，WWOX转基因的细胞表现出促凋亡的表型。我们进一步表明，WWOX的表达降低了膜整合素α(3)蛋白，但不降低整合素α(3)的mRNA水平，并且PEO1细胞与纤维连接蛋白的黏附主要是通过整合素α(3)介导的。因此，我们认为WWOX通过调节肿瘤细胞与细胞外基质之间的相互作用，并通过诱导分离细胞的凋亡来发挥卵巢肿瘤抑制作用。与此一致，WWOX对PEO1致瘤性的抑制可以通过将这些肿瘤细胞植入Matrigel来部分克服。这些数据表明WWOX的丢失可能在人卵巢癌细胞的腹膜扩散中起作用。[癌症资源2009；69(11)：4835-42]
The WW domain-containing oxidoreductase (WWOX) gene Is located at FRA16D, a common fragile site involved in human cancer. Targeted deletion of Wwox in mice causes increased spontaneous tumor incidence, confirming that WWOX is a bona fide tumor suppressor gene. We show that stable transfection of WWOX into human PEO1 ovarian cancer cells, containing homozygous WWOX deletion, abolishes in vivo tumorigenicity, but this does not correlate with alteration of in vitro growth. Rather, WWOX restoration in PEO1, or WWOX overexpression in SKOV3 ovarian cancer cells, results in reduced attachment and migration on fibronectin, an extracellular matrix component linked to peritoneal metastasis. Conversely, siRNA-mediated knockdown of endogenous WWOX in A2780 ovarian cancer cells increases adhesion to fibronectin. In addition, whereas there is no WWOX-dependent difference in cell death in adherent cells, WWOX-transfected cells in suspension culture display a proapoptotic phenotype. We further show that WWOX expression reduces membranous integrin alpha(3) protein but not integrin alpha(3) mRNA levels, and that adhesion of PEO1 cells to fibronectin is predominantly mediated through integrin alpha(3). We therefore propose that WWOX acts as an ovarian tumor suppressor by modulating the interaction between tumor cells and the extracellular matrix and by inducing apoptosis in detached cells. Consistent with this, the suppression of PEO1 tumorigenicity by WWOX can be partially overcome by implanting these tumor cells in Matrigel. These data suggest a possible role for the loss of WWOX in the peritoneal dissemination of human ovarian cancer cells. [Cancer Res 2009;69(11):4835-42]