miR-146b-5p mediates p16-dependent repression of IL-6 and suppresses paracrine procarcinogenic effects of breast stromal fibroblasts.
miR-146b-5p mediates p16-dependent repression of IL-6 and suppresses paracrine procarcinogenic effects of breast stromal fibroblasts.
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DOI：
10.18632/oncotarget.4933
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发表时间：
2015-10-06
期刊：
影响因子：
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通讯作者：
Aboussekhra A
中科院分区：
文献类型：
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作者：
Al-Ansari MM;Aboussekhra A
越来越多的证据支持活性基质成纤维细胞在乳腺癌发生和扩散中的关键作用。然而，调节因素和调节机制仍然不明确。我们在此表明肿瘤抑制因子 p16INK4A 蛋白通过抑制 IL-6 的表达/分泌来抑制乳腺基质成纤维细胞的致癌作用。事实上，p16INK4A 在 mRNA 和蛋白质水平上抑制 IL-6。这种效应是通过 miR-146b-5p 介导的，miR-146b-5p 通过 IL-6 3'UTR 处的特定序列抑制 IL-6 表达。此外，我们提供了明确的证据，表明 miR-146b-5p 抑制足以反式激活乳腺基质成纤维细胞，从而以旁分泌方式促进乳腺癌细胞的上皮细胞向间质细胞转化。相比之下，活性成纤维细胞中 miR-146b-5p 的异位表达消除了其致癌作用。与从同一患者分离的无癌组织中的正常邻近对应物相比，癌症相关成纤维细胞中前 miR-146b-5p 及其成熟形式的水平降低，揭示了 miR-146b-5p 抑制的生理重要性。有趣的是，用姜黄素处理活性乳腺基质成纤维细胞，增加了编码CDKN2A mRNA和miR-146b-5p的p16INK4A的水平，并抑制了IL-6，这证实了这两种肿瘤抑制分子对IL-6的抑制作用，并显示了癌症相关活性成纤维细胞可能的“正常化”。这些结果表明，miR-146b-5p 通过抑制 IL-6 具有非细胞自主肿瘤抑制功能，这表明靶向乳腺基质成纤维细胞中的这种 microRNA 可能具有巨大的治疗价值。
Increasing evidence support the critical roles of active stromal fibroblasts in breast cancer development and spread. However, the mediators and the mechanisms of regulation are still not well defined. We have shown here that the tumor suppressor p16INK4A protein inhibits the pro-carcinogenic effects of breast stromal fibroblasts through repressing the expression/secretion of IL-6. Indeed, p16INK4A suppresses IL-6 at the mRNA and protein levels. This effect is mediated trough miR-146b-5p, which inhibits IL-6 expression through a specific sequence at the IL-6 3′UTR. In addition, we present clear evidence that miR-146b-5p inhibition is sufficient to transactivate breast stromal fibroblasts, which promote epithelial-to-mesenchymal-transition in breast cancer cells in a paracrine manner. By contrast, ectopic expression of miR-146b-5p in active fibroblasts abrogated their pro-carcinogenic effects. The physiological importance of miR-146b-5p inhibition was revealed by showing that the levels of pre-miR-146b-5p as well as its mature form are reduced in cancer-associated fibroblasts as compared with their normal adjacent counterparts from cancer-free tissues isolated from the same patients. Interestingly, treatment of active breast stromal fibroblasts with curcumin increased the level of the p16INK4A coding CDKN2A mRNA and miR-146b-5p and suppressed IL-6, which confirms the repressive effect of these two tumor suppressor molecules on IL-6, and shows the possible “normalization” of cancer-related active fibroblasts. These results show that miR-146b-5p has non-cell-autonomous tumor suppressor function through inhibition of IL-6, suggesting that targeting this microRNA in breast stromal fibroblasts could be of great therapeutic value.