The inflammatory/cancer-related IL-6/STAT3/NF-κB positive feedback loop includes AUF1 and maintains the active state of breast myofibroblasts.
The inflammatory/cancer-related IL-6/STAT3/NF-κB positive feedback loop includes AUF1 and maintains the active state of breast myofibroblasts.
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DOI：
10.18632/oncotarget.9633
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发表时间：
2016-07-05
期刊：
影响因子：
--
通讯作者：
Aboussekhra A
中科院分区：
文献类型：
--
作者：
Hendrayani SF;Al-Harbi B;Al-Ansari MM;Silva G;Aboussekhra A
IL-6/STAT 3/NF-κB正反馈环将炎症与癌症联系起来，并将细胞维持在转化状态。同样，癌症相关的肌纤维母细胞即使在没有癌细胞的情况下也保持活性。然而，这种持续活跃状态的分子基础仍然难以捉摸。我们在此发现，乳腺癌细胞和IL-6通过刺激阳性IL-6/STAT 3/NF-κB反馈环持续激活乳腺基质成纤维细胞。培养物中IL-6的瞬时中和抑制了这种信号传导回路，并使成肌纤维细胞恢复到正常状态，这也暗示了IL-6自分泌反馈回路的含义。重要的是，IL-6/STAT 3/NF-κB促炎回路在从乳腺癌患者分离的癌症相关成纤维细胞中也是活跃的。在活性成纤维细胞中通过特异性siRNA瞬时抑制STAT 3持续降低RNA结合蛋白AUF 1的水平，阻断环并使这些细胞正常化。此外，我们提出了明确的证据表明，AUF 1也是这个正反馈回路的一部分。有趣的是，用咖啡因处理乳腺肌成纤维细胞，其先前已显示持续抑制活性乳腺基质成纤维细胞，通过有效和持续抑制STAT 3，AKT，lin 28 B和AUF 1阻断了正反馈回路。这些结果表明，IL-6/STAT 3/NF-κB正反馈环包括AUF 1，并负责癌症相关成纤维细胞的持续活性状态。我们还表明，正常化肌成纤维细胞，这可能是很大的治疗价值，是可能通过抑制这种致癌回路。
The IL-6/STAT3/NF-κB positive feedback loop links inflammation to cancer and maintains cells at a transformed state. Similarly, cancer-associated myofibroblats remains active even in absence of cancer cells. However, the molecular basis of this sustained active state remains elusive. We have shown here that breast cancer cells and IL-6 persistently activate breast stromal fibroblasts through the stimulation of the positive IL-6/STAT3/NF-κB feedback loop. Transient neutralization of IL-6 in culture inhibited this signaling circuit and reverted myofibrobalsts to a normalized state, suggesting the implication of the IL-6 autocrine feedback loop as well. Importantly, the IL-6/STAT3/NF-κB pro-inflammatory circuit was also active in cancer-associated fibroblasts isolated from breast cancer patients. Transient inhibition of STAT3 by specific siRNA in active fibroblasts persistently reduced the level of the RNA binding protein AUF1, blocked the loop and normalized these cells. Moreover, we present clear evidence that AUF1 is also part of this positive feedback loop. Interestingly, treatment of breast myofibroblasts with caffeine, which has been previously shown to persistently inhibit active breast stromal fibroblasts, blocked the positive feedback loop through potent and sustained inhibition of STAT3, AKT, lin28B and AUF1. These results indicate that the IL-6/STAT3/NF-κB positive feedback loop includes AUF1 and is responsible for the sustained active status of cancer-associated fibroblasts. We have also shown that normalizing myofibroblasts, which could be of great therapeutic value, is possible through the inhibition of this procarcinogenic circuit.
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影响因子：
8
作者：
Al-Ansari, M. M.;Hendrayani, S. F.;Shehata, A. I.;Aboussekhra, A.
通讯作者：
Aboussekhra, A.
DOI：
10.1186/bcr1680
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Berishaj M;Gao SP;Ahmed S;Leslie K;Al-Ahmadie H;Gerald WL;Bornmann W;Bromberg JF
通讯作者：
Bromberg JF
影响因子：
3.7
作者：
Al-Ansari MM;Aboussekhra A
通讯作者：
Aboussekhra A
影响因子：
0.7
作者：
Aboussekhra, Abdelilah
通讯作者：
Aboussekhra, Abdelilah
影响因子：
7.3
作者：
Franco OE;Shaw AK;Strand DW;Hayward SW
通讯作者：
Hayward SW