p53 attenuates cancer cell migration and invasion through repression of SDF-1/CXCL12 expression in stromal fibroblasts
p53 attenuates cancer cell migration and invasion through repression of SDF-1/CXCL12 expression in stromal fibroblasts
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DOI：
10.1158/0008-5472.can-06-2323
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发表时间：
2006-11-15
期刊：
影响因子：
11.2
通讯作者：
Oren, Moshe
中科院分区：
文献类型：
--
作者：
Moskovits, Neta;Kalinkovich, Alexander;Oren, Moshe
p53肿瘤抑制因子是对抗癌症的主要屏障。在很大程度上，这是由于它能够保持基因组稳定性，并通过细胞自主机制从复制库中消除癌细胞。然而，除了其在恶性肿瘤细胞内的功能外，p53还可以发挥非细胞自主作用，有助于肿瘤抑制。我们现在报道，p53可以抑制人和小鼠来源的培养成纤维细胞中趋化因子SDF-1的产生。这是由于p53介导的SDF-1 mRNA的下调，其可在药物Nutlin-3激活p53时加剧。SDF-1促进表达其同源受体CXCR 4的细胞的迁移和侵袭。事实上，由p53缺陷型成纤维细胞调节的培养基诱导癌细胞朝向增加的定向迁移和侵袭，这在很大程度上被CXCR 4拮抗剂肽逆转。由于间质成纤维细胞产生的SDF-1在癌症进展和转移中起着重要作用，我们的研究结果表明，p53抑制间质成纤维细胞的能力。SDF-1的产生可能是其发挥非细胞自主肿瘤抑制功能的重要机制。
The p53 tumor suppressor acts as a major barrier against cancer. To a large extent, this is due to its ability to maintain genome stability and to eliminate cancer cells from the replicative pool through cell-autonomous mechanisms. However, in addition to its well-documented functions within the malignant cancer cell, p53 can also exert non-cell-autonomous effects that contribute to tumor suppression. We now report that p53 can suppress the production of the chemokine SDF-1 in cultured fibroblasts of both human and mouse origin. This is due to a p53-mediated down-regulation of SDF-1 mRNA, which can be exacerbated on activation of p53 by the drug Nutlin-3. SDF-1 promotes the migration and invasiveness of cells that express its cognate receptor CXCR4. Indeed, medium conditioned by p53-deficient fibroblasts induces cancer cells towards increased directional migration and invasiveness, which are largely reversed by CXCR4 antagonist peptides. Because SDF-1 produced by stromal fibroblasts plays an important role in cancer progression and metastasis, our findings suggest that the ability of p53 to suppress stromal. SDF-1 production may be an important mechanism whereby it does its non-cell-autonomous tumor suppressor function.