Inflammatory factor TNF-α promotes the growth of breast cancer via the positive feedback loop of TNFR1/NF-κB (and/or p38)/p-STAT3/HBXIP/TNFR1.
Inflammatory factor TNF-α promotes the growth of breast cancer via the positive feedback loop of TNFR1/NF-κB (and/or p38)/p-STAT3/HBXIP/TNFR1.
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炎症因子TNF-α通过TNFR1/NF-κB（和/或p38）/p-STAT3/HBXIP/TNFR1的正反馈环促进乳腺癌生长
DOI：
10.18632/oncotarget.16873
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发表时间：
2017-08-29
期刊：
影响因子：
--
通讯作者：
Ye L
中科院分区：
文献类型：
--
作者：
Cai X;Cao C;Li J;Chen F;Zhang S;Liu B;Zhang W;Zhang X;Ye L
在炎症和癌症发展之间的联系中，肿瘤坏死因子-α (TNF-α) 有助于肿瘤发生。然而，其根本机制仍然知之甚少。在这项研究中，我们报告 TNF-α 通过上调癌蛋白乙型肝炎 X 相互作用蛋白 (HBXIP) 来促进乳腺癌的生长。我们的数据显示临床乳腺癌组织中TNF-α的水平与HBXIP的水平呈正相关。此外，TNF-α 可以上调乳腺癌细胞中的 HBXIP。有趣的是，沉默 TNF-α 受体 1 (TNFR1) 可阻断 TNF-α 对 HBXIP 的作用。从机制上讲，我们发现TNF-α可以通过激活转录因子信号转导子和转录激活子3（STAT3）来增加HBXIP启动子的活性。此外，核因子κB (NF-κB) 和/或p38 信号传导增加了细胞中p-STAT3 的水平。引人注目的是，HBXIP 还可以上调 TNFR1，形成 TNFR1/NF-κB（和/或 p38）/p-STAT3/HBXIP/TNFR1 的正反馈回路。值得注意的是，TNF-α 能够通过驱动环路上调 TNFR1。在功能上，我们证明了 HBXIP 的敲低在体外和体内显着消除了 TNF-α 介导的乳腺癌生长。因此，我们得出结论，TNF-α通过TNFR1/NF-κB（和/或p38）/p-STAT3/HBXIP/TNFR1的正反馈环促进乳腺癌的生长。我们的发现为TNF-α驱动癌蛋白HBXIP在乳腺癌发生过程中的机制提供了新的见解。
In the connection between inflammation and cancer development, tumor necrosis factor-alpha (TNF-α) contributes to the tumorigenesis. However, the underlying mechanism remains poorly understood. In this study, we report that TNF-α enhances the growth of breast cancer through up-regulation of oncoprotein hepatitis B X-interacting protein (HBXIP). Our data showed that the levels of TNF-α were positively related to those of HBXIP in clinical breast cancer tissues. Moreover, TNF-α could up-regulate HBXIP in breast cancer cells. Interestingly, silencing of TNF-α receptor 1 (TNFR1) blocked the effect of TNF-α on HBXIP. Mechanistically, we revealed that TNF-α could increase the activities of HBXIP promoter through activating transcriptional factor signal transducer and activator of transcription 3 (STAT3). In addition, nuclear factor kappa B (NF-κB) and/or p38 signaling increased the levels of p-STAT3 in the cells. Strikingly, HBXIP could also up-regulate TNFR1, forming a positive feedback loop of TNFR1/NF-κB (and/or p38)/p-STAT3/HBXIP/TNFR1. Notably, TNF-α was able to up-regulate TNFR1 through driving the loop. In function, we demonstrated that the knockdown of HBXIP remarkably abolished the growth of breast cancer mediated by TNF-α in vitro and in vivo. Thus, we conclude that TNF-α promotes the growth of breast cancer through the positive feedback loop of TNFR1/NF-κB (and/or p38)/p-STAT3/HBXIP/TNFR1.Our finding provides new insights into the mechanism by which TNF-α drives oncoprotein HBXIP in the development of breast cancer.
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