Integrity of SOS1/EPS8/ABI1 tri-complex determines ovarian cancer metastasis.
Integrity of SOS1/EPS8/ABI1 tri-complex determines ovarian cancer metastasis.
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DOI：
10.1158/0008-5472.can-10-2394
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发表时间：
2010-12-01
期刊：
影响因子：
11.2
通讯作者：
Huang S
中科院分区：
文献类型：
--
作者：
Chen H;Wu X;Pan ZK;Huang S
卵巢癌主要局限于腹膜腔内，其转移常与恶性腹水的形成有关。由于溶血磷脂酸(LPA)在卵巢癌患者的腹水中含量较高，并能有效地刺激细胞迁移，我们推测LPA刺激的细胞迁移可能在卵巢癌转移中发挥重要作用。在这里，我们表明，只有那些有LPA迁移反应的卵巢癌细胞株才会发生腹膜转移定植。LPA刺激的细胞迁移是转移定植所必需的，因为LPA受体1(LPAR1)的敲除取消了这一事件。然而，转移潜能的差异并不是由于LPAR1的缺失造成的，因为转移株和非转移株表达相似水平的LPAR1。相反，我们发现LPA只能在转移细胞中激活RAC，而卵巢癌细胞的转移定植需要RAC活性。这些结果表明，LPA诱导的Rac活化是卵巢癌转移的先决条件。在转移细胞中，SOS1/Eps8/ABI1三元复合体促进了Rac的激活，该三元复合体的完整性对于LPA刺激的细胞迁移和转移定植是必不可少的。我们发现，在非转移性卵巢癌细胞中，至少有一个SOS1/Eps8/ABI1三元复合体缺失，而重新表达缺失的一个使其具有转移能力。重要的是，SOS1、Eps8和ABI1的共同表达，而不是SOS1/Eps8/ABI1三个复合体中任何一个成员的单独表达，与卵巢癌患者的晚期和较短的生存期相关。我们的研究表明SOS1/Eps8/ABI1三个复合体的完整性是卵巢癌转移的决定因素。
Ovarian cancer is mainly confined in peritoneal cavity and its metastasis is often associated with the formation of malignant ascites. As lysophosphatidic acid (LPA) is present at high levels in ovarian cancer patients’ ascites and potently stimulates cell migration, we reason that LPA-stimulated cell migration may play an important role in ovarian cancer metastasis. Here, we show that only those ovarian cancer cell lines with LPA migratory response undergo peritoneal metastatic colonization. LPA-stimulated cell migration is required for metastatic colonization because knockdown of LPA receptor 1 (LPAR1) abolishes this event. However, the difference in metastatic potentials is not caused by the absence of LPAR1 because both metastatic and non-metastatic lines express similar level of LPAR1. Instead, we find that LPA can only activate Rac in metastatic cells and that metastatic colonization of ovarian cancer cells necessitates Rac activity. These results thus suggest that LPA-induced Rac activation is a prerequisite for ovarian cancer metastasis. In metastatic cells, Rac activation is facilitated by SOS1/EPS8/ABI1 tri-complex and the integrity of this tri-complex is essential for LPA-stimulated cell migration and metastatic colonization. We show that at least one member of SOS1/EPS8/ABI1 tri-complex is absent in non-metastatic ovarian cancer cells and re-expressing the missing one conferred them with metastatic capability. Importantly, co-expression of SOS1, EPS8 and ABI1, but not the expression of any individual member of SOS1/EPS8/ABI1 tri-complex, correlates with advanced stages and shorter survival of ovarian cancer patients. Our study implicates that the integrity of SOS1/EPS8/ABI1 tri-complex is a determinant of ovarian cancer metastasis.