Slug promotes survival during metastasis through suppression of Puma-mediated apoptosis.
Slug promotes survival during metastasis through suppression of Puma-mediated apoptosis.
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DOI：
10.1158/0008-5472.can-13-2591
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发表时间：
2014-07-15
期刊：
影响因子：
11.2
通讯作者：
Hazan RB
中科院分区：
文献类型：
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作者：
Kim S;Yao J;Suyama K;Qian X;Qian BZ;Bandyopadhyay S;Loudig O;De Leon-Rodriguez C;Zhou ZN;Segall J;Macian F;Norton L;Hazan RB
肿瘤细胞必须克服凋亡才能在转移性播散和远端器官定植中存活。在这里，我们显示在多瘤中T乳腺肿瘤模型，N-钙粘蛋白表达导致Slug上调，这反过来又促进癌细胞的生存。相对于原发性肿瘤，Slug在转移瘤中显著上调。与转移中的作用一致，癌细胞中的Slug敲低通过降低转移部位的细胞存活来抑制肺定植，但对肿瘤细胞侵袭或外渗没有影响。为了支持这一观点，通过shRNA抑制Slug，使肿瘤细胞对DNA损伤引起的凋亡敏感，导致caspase-3和PARP裂解。发现Slug的促存活作用是由Slug直接抑制促凋亡基因Puma引起的。与Slug-Puma轴在转移中的关键作用一致，在Slug敲低细胞中通过RNA干扰抑制Puma挽救了肺定殖，而在对照肿瘤细胞中Puma过表达抑制了肺转移。在人乳腺癌细胞中证实了Slug-Puma轴的存活功能，其中Slug敲低增加了Puma表达并抑制了肺定殖。这项研究证明了Slug在癌细胞存活中的关键作用，这意味着Slug-Puma轴的破坏可能会影响转移细胞的存活。
Tumor cells must overcome apoptosis to survive throughout metastatic dissemination and distal organ colonization. Here we show in the Polyoma Middle T mammary tumor model that N-cadherin expression causes Slug upregulation, which in turn promotes carcinoma cell survival. Slug was dramatically upregulated in metastases relative to primary tumors. Consistent with a role in metastasis, Slug knockdown in carcinoma cells suppressed lung colonization by decreasing cell survival at metastatic sites, but had no effect on tumor cell invasion or extravasation. In support of this idea, Slug inhibition by shRNA, sensitized tumor cells to apoptosis by DNA damage, resulting in caspase-3 and PARP cleavage. The pro-survival effect of Slug was found to be caused by direct repression of the pro-apoptotic gene, Puma, by Slug. Consistent with a pivotal role for a Slug-Puma axis in metastasis, inhibition of Puma by RNA interference in Slug-knockdown cells rescued lung colonization, whereas Puma overexpression in control tumor cells suppressed lung metastasis. The survival function of the Slug-Puma axis was confirmed in human breast cancer cells, where Slug knockdown increased Puma expression and inhibited lung colonization. This study demonstrates a pivotal role for Slug in carcinoma cell survival, implying that disruption of the Slug-Puma axis may impinge on the survival of metastatic cells.