p16(INK4A) represses the paracrine tumor-promoting effects of breast stromal fibroblasts.
p16(INK4A) represses the paracrine tumor-promoting effects of breast stromal fibroblasts.
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DOI：
10.1038/onc.2012.270
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发表时间：
2013-05-02
期刊：
影响因子：
8
通讯作者：
Aboussekhra, A.
中科院分区：
文献类型：
--
作者：
Al-Ansari, M. M.;Hendrayani, S. F.;Shehata, A. I.;Aboussekhra, A.
癌症相关成纤维细胞（CAFs），乳腺癌相关基质中最丰富和可能最活跃的细胞成分，通过旁分泌效应促进癌变;然而，分子基础仍然难以捉摸。我们在这里已经表明，p16 INK 4A的表达减少83% CAFs相比，其正常的相邻对应物的无癌组织分离自相同的患者。这种降低主要是由于CAF中CDKN 2A mRNA的AUF 1依赖性较高的周转。重要的是，使用特异性siRNA下调p16 INK 4A激活乳腺成纤维细胞，并增加基质细胞衍生因子1（SDF-1）和基质金属蛋白酶（MMP）-2的表达/分泌水平。因此，用这些细胞调节的培养基刺激上皮细胞的增殖。此外，乳腺癌细胞的迁移/侵袭也以SDF-1依赖的方式增强。这种作用是通过诱导上皮-间充质转化状态介导的。相反，通过异位表达或AUF 1下调增加p16 INK 4A水平，降低SDF-1和MMP-2的分泌水平，并抑制CAFs的促癌作用。此外，p16 INK 4A缺陷的成纤维细胞加速了小鼠乳腺肿瘤异种移植物的形成和生长速率。重要的是，在p16 INK 4A缺陷型成纤维细胞存在下形成的肿瘤表现出更高水平的活性Akt、考克斯-2、MMP-2和MMP-9，与在p16 INK 4A有效型成纤维细胞存在下形成的异种移植物相比，显示出更大的侵袭性。这些结果首次表明，乳腺基质成纤维细胞中p16 INK 4A的下调是其活化的重要一步。
Cancer-associated fibroblasts (CAFs), the most abundant and probably the most active cellular component of breast cancer-associated stroma, promote carcinogenesis through paracrine effects; however, the molecular basis remains elusive. We have shown here that p16INK4A expression is reduced in 83% CAFs as compared with their normal adjacent counterparts cancer-free tissues isolated from the same patients. This decrease is mainly due to AUF1-dependent higher turnover of the CDKN2A mRNA in CAFs. Importantly, p16INK4A downregulation using specific siRNA activated breast fibroblasts and increased the expression/secretion levels of stromal cell-derived factor 1 (SDF-1) and matrix metalloproteinase (MMP)-2. Consequently, media conditioned with these cells stimulated the proliferation of epithelial cells. Furthermore, the migration/invasion of breast cancer cells was also enhanced in an SDF-1-dependent manner. This effect was mediated through inducing an epithelial–mesenchymal transition state. By contrast, increase in p16INK4A level through ectopic expression or AUF1 downregulation, reduced the secreted levels of SDF-1 and MMP-2 and suppressed the pro-carcinogenic effects of CAFs. In addition, p16INK4A-defective fibroblasts accelerated breast tumor xenograft formation and growth rate in mice. Importantly, tumors formed in the presence of p16INK4A-defective fibroblasts exhibited higher levels of active Akt, Cox-2, MMP-2 and MMP-9, showing their greater aggressiveness as compared with xenografts formed in the presence of p16INK4A-proficient fibroblasts. These results provide the first indication that p16INK4A downregulation in breast stromal fibroblasts is an important step toward their activation.
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