Jak-STAT3 pathway triggers DICER1 for proteasomal degradation by ubiquitin ligase complex of CUL4ADCAF1 to promote colon cancer development
Jak-STAT3 pathway triggers DICER1 for proteasomal degradation by ubiquitin ligase complex of CUL4ADCAF1 to promote colon cancer development
复制标题
Jak-STAT3通路通过CUL4ADCAF1的泛素连接酶复合物触发DICER1进行蛋白酶体降解，促进结肠癌的发展
DOI：
10.1016/j.canlet.2016.02.055
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发表时间：
2016-06-01
期刊：
影响因子：
9.7
通讯作者：
Ma, Jian
中科院分区：
文献类型：
--
作者：
Ren, Weiguo;Shen, Shourong;Ma, Jian
慢性肠道炎症与结肠癌的发展密切相关，STAT3 似乎在慢性炎症与结肠癌进展之间架起了桥梁。在这里，我们发现 DICER1 响应 IL-6 或 LPS 刺激而显着下调，并确定了结肠癌细胞中 CUL4A（DCAF1）泛素连接酶复合物的蛋白酶体降解导致 DICER1 下调的新机制。同时，PI3K-AKT信号通路磷酸化DICER1并促进其蛋白酶体降解。 CUL4A(DCAF1)对DICER1的调节影响细胞生长和凋亡，这是由IL-6激活的Jak-STAT3通路控制的。 CUL4A(DCAF1)泛素连接酶复合物的干预导致DICER1和microRNA的表达水平波动，从而影响小鼠异种移植模型中的肿瘤生长。一组被IL-6刺激下调的microRNA被siRNA-CUL4A拯救，它们的预测功能涉及细胞增殖、凋亡和运动的调节。此外，临床样本分析显示，DICER1 表达降低与人类结肠癌中 STAT3 激活和癌症进展呈负相关。 DICER1 和 p-STAT3 表达水平与结肠癌患者的 5 年总生存率相关。因此，本研究提出，炎症诱导的 Jak-STAT3 信号传导通过 CUL4A(DCAF1) 泛素连接酶复合物对 DICER1 的蛋白酶体降解，导致结肠癌的发生，这为结肠癌提供了新的治疗机会。 (C) 2016 Elsevier Ireland Ltd. 保留所有权利。
Chronic intestinal inflammation is closely associated with colon cancer development and STAT3 seems to take center stage in bridging chronic inflammation to colon cancer progress. Here, we discovered that DICER1 was significantly downregulated in response to IL-6 or LPS stimulation and identified a novel mechanism for DICER1 downregulation via proteasomal degradation by ubiquitin ligase complex of CUL4A(DCAF1) in colon cancer cells. Meanwhile, PI3K-AKT signaling pathway phosphorylated DICER1 and contributed to its proteasomal degradation. The regulation of DICER1 by CUL4A(DCAF1) affected cell growth and apoptosis which is controlled by IL-6 activated Jak-STAT3 pathway. Intervention of CUL4A(DCAF1) ubiquitin ligase complex led to fluctuation in expression levels of DICER1 and microRNAs, and thus affected tumor growth in a mouse xenograft model. A panel of microRNAs that were downregulated by IL-6 stimulation was rescued by siRNA-CUL4A, and their predicated functions are involved in regulation of cell proliferation, apoptosis and motility. Furthermore, clinical specimen analysis revealed that decreased DICER1 expression was negatively correlated with STAT3 activation and cancer progression in human colon cancers. DICER1 and p-STAT3 expression levels correlated with 5-year overall survival of colon cancer patients. Consequently, this study proposes that inflammation-induced Jak-STAT3 signaling leads to colon cancer development through proteasomal degradation of DICER1 by ubiquitin ligase complex of CUL4A(DCAF1), which suggests a novel therapeutic opportunity for colon cancer. (C) 2016 Elsevier Ireland Ltd. All rights reserved.