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Targeting TRIM3 deletion-induced tumor-associated lymphangiogenesis prohibits lymphatic metastasis in esophageal squamous cell carcinoma

Oncogene volume 38, pages 2736–2749 (2019)Cite this article

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Abstract

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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Acknowledgements

This work was supported by Natural Science Foundation of China (No. 81830082, 91740119, 91529301, 81621004, 91740118, 81773106 and 81530082); Guangzhou Science and Technology Plan Projects (201803010098); Natural Science Foundation of Guangdong Province (2018B030311009 and 2016A030308002); The Fundamental Research Funds for the Central Universities [No. 17ykjc02].

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  1. These authors contributed equally: Jinrong Zhu, Geyan Wu, Zunfu Ke

Authors and Affiliations

  1. Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou,Guangdong, China

    Jinrong Zhu, Geyan Wu, Lixue Cao, Ziwen Li, Qiaojia Li, Junhao Zhou, Zhanyao Tan & Jun Li

  2. Department of biochemistry, Zhongshan School of medicine, Sun Yat-sen University, Guangzhou, Guangdong, China

    Jinrong Zhu, Miaoling Tang & Jun Li

  3. State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China

    Geyan Wu & Libing Song

  4. Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangzhou, Guangdong, 510060, China

    Zunfu Ke

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Zhu, J., Wu, G., Ke, Z. et al. Targeting TRIM3 deletion-induced tumor-associated lymphangiogenesis prohibits lymphatic metastasis in esophageal squamous cell carcinoma. Oncogene 38, 2736–2749 (2019). https://doi.org/10.1038/s41388-018-0621-5

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