Phosphatase PRL-3 is a direct regulatory target of TGFbeta in colon cancer metastasis.
Phosphatase PRL-3 is a direct regulatory target of TGFbeta in colon cancer metastasis.
复制标题
磷酸酶 PRL-3 是结肠癌转移中 TGFbeta 的直接调节靶点。
DOI：
10.1158/0008-5472.can-10-1487
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发表时间：
2011-01-01
期刊：
影响因子：
11.2
通讯作者：
Wang J
中科院分区：
文献类型：
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作者：
Jiang Y;Liu XQ;Rajput A;Geng L;Ongchin M;Zeng Q;Taylor GS;Wang J
肿瘤转移是导致大多数癌症死亡的原因，但机制上的理解和治疗选择仍然有限。磷酸酶PRL-3的过度表达与结肠癌的转移有关。在这里，我们展示了PRL-3是转化生长因子β(转化生长因子β)信号的直接靶点，它广泛地参与了肿瘤的进展和转移。我们发现转化生长因子β抑制PRL-3的表达是通过在启动子活性水平上依赖Smad抑制PRL-3转录而实现的。PRL-3激活可刺激PI3K/AKT信号转导，从而对应激诱导的细胞凋亡产生抵抗作用。PRL-3过表达促进了结肠癌原位小鼠模型的转移定植，而PRK-3基因敲除降低了转移潜能。转移表型的改变不是原发肿瘤发展或局部侵袭的衍生品，而是与PRL-3介导的细胞存活有关。我们的发现提示，抑制PRL-3的表达可能是转化生长因子β抑制结肠癌转移的重要机制。此外，我们的研究结果表明，转化生长因子β信号的缺失，通常发生在结肠癌进展过程中，足以激活PRL-3介导的细胞生存途径，从而选择性地促进转移。因此，我们的发现的一个主要含义是，PRL-3拮抗剂可能为结肠癌患者的抗转移治疗提供重要的价值。
Metastasis causes most deaths from cancer yet mechanistic understanding and therapeutic options remain limited. Overexpression of the phosphatase PRL-3 is associated with metastasis of colon cancer. Here we show here that PRL-3 is a direct target of signaling by transforming growth factor β (TGFβ), which is broadly implicated in progression and metastasis. We found that suppression of PRL-3 expression by TGFβ was mediated by Smad-dependent inhibition of PRL-3 transcription at the level of promoter activity. PRL-3 activation stimulated PI3K/AKT signaling which caused resistance to stress-induced apoptosis. PRL-3 overexpression promoted metastatic colonization in an orthotopic mouse model of colon cancer, whereas PRK-3 knockdown reduced metastatic potential. Altered metastatic phenotypes were not derivative of primary tumor development or local invasion but could be attributed to PRL-3-mediated cell survival. Our findings suggest that inhibiting PRL-3 expression might be an important mechanism through which TGFβ suppresses metastasis in colon cancer. Additionally, our findings suggest that loss of TGFβ signaling, which occurs commonly during colon cancer progression, is sufficient to activate a PRL-3-mediated cell survival pathway that can selectively promote metastasis. Therefore, a major implication of our findings is that PRL-3 antagonists may offer significant value for anti-metastatic therapy in patients with colon cancer.