Targeting TRIM3 deletion-induced tumor-associated lymphangiogenesis prohibits lymphatic metastasis in esophageal squamous cell carcinoma
Targeting TRIM3 deletion-induced tumor-associated lymphangiogenesis prohibits lymphatic metastasis in esophageal squamous cell carcinoma
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靶向 TRIM3 缺失诱导的肿瘤相关淋巴管生成可抑制食管鳞状细胞癌的淋巴转移
DOI：
10.1038/s41388-018-0621-5
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发表时间：
2018-12
期刊：
影响因子：
8
通讯作者：
Li Jun
中科院分区：
文献类型：
--
作者：
Zhu Jinrong;Wu Geyan;Ke Zunfu;Cao Lixue;Tang Miaoling;Li Ziwen;Li Qiaojia;Zhou Junhao;Tan Zhanyao;Song Libing;Li Jun
肿瘤相关淋巴管生成因其对淋巴结转移的潜在贡献而引起越来越多的关注。然而，肿瘤中淋巴管生成的分子机制仍然难以捉摸。在本研究中，我们发现TRIM3直接与E3连接酶依赖的进口蛋白α3和α-肌动蛋白4 （ACTN4）的蛋白酶体转换相互作用并诱导其在有序水平上控制核因子κB （NF-κB）活性。杂合缺失介导的TRIM3下调通过破坏NF-κB- i -κB -α负反馈回路导致NF-κB组成性激活，并通过促进NF-κB/p65在Arg30和Arg35处的对称二甲基精氨酸修饰增强p65 dna结合亲和力和转录活性，从而促进食管鳞状细胞癌（ESCC）细胞的淋巴转移。使用用于治疗多发性硬化的药物Tecfidera，通过降低NF-κB/ACTN4相互作用和降低对称二甲基化的NF-κB水平，恢复了对NF-κB的负反馈抑制，从而在体外和体内抑制ESCC淋巴转移。综上所述，我们的研究结果揭示了肿瘤中构成性NF-κB激活的新机制，可能代表了治疗ESCC淋巴转移的一种有吸引力的策略。
Tumor-associated lymphangiogenesis has attracted increasing attention because of its potential contribution to lymph node metastasis. However, the molecular mechanisms underlying lymphangiogenesis in cancer remains elusive. In the current study, we demonstrate that tripartite motif-containing 3 (TRIM3) directly interacts with and induces E3 ligase-dependent proteasomal turnover of importin α3 and α-Actinin-4 (ACTN4), which controls nuclear factor kappa B (NF-κB) activity at a well-ordered level. Heterozygous deletion-mediated TRIM3 downregulation led to NF-κB constitutive activation through disruption of the NF-κB-IκB-α negative feedback loop and enhancement of the p65 DNA-binding affinity and transcriptional activity via promoting symmetrical dimethylarginine modification of NF-κB/p65 at Arg30 and Arg35, which consequently promoted lymphatic metastasis of esophageal squamous cell carcinoma (ESCC) cells. Treatment with Tecfidera, a medication used to treat multiple sclerosis, restored the negative feedback inhibition of NF-κB by reducing the NF-κB/ACTN4 interaction and decreasing symmetrically dimethylated NF-κB levels, resulting in inhibition of ESCC lymphatic metastasis both in vitro and in vivo. Taken together, our results uncover a novel mechanism for constitutive NF-κB activation in cancer and may represent an attractive strategy to treat ESCC lymphatic metastasis.
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NF-κB：通过甲基化调节。
影响因子：
11.2
作者：
Lu T;Stark GR
通讯作者：
Stark GR
影响因子：
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作者：
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20.3
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影响因子：
4.8
作者：
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Frasor, Jonna
影响因子：
3.8
作者：
Schoppmann, Sebastian F.;Jesch, Bettina;Birner, Peter
通讯作者：
Birner, Peter