Targeting TRIM3 deletion-induced tumor-associated lymphangiogenesis prohibits lymphatic metastasis in esophageal squamous cell carcinoma
| Autor: | Miaoling Tang, Geyan Wu, Qiaojia Li, Lixue Cao, Zunfu Ke, Jun Li, Zhanyao Tan, Libing Song, Ziwen Li, Jinrong Zhu, Junhao Zhou |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Esophageal Neoplasms Importin Biology Cell Line 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation NF-KappaB Inhibitor alpha In vivo Genetics medicine Humans Actinin Lymphangiogenesis Molecular Biology Multiple sclerosis NF-kappa B Cancer medicine.disease In vitro 030104 developmental biology Cell culture 030220 oncology & carcinogenesis Lymphatic Metastasis Cancer research Esophageal Squamous Cell Carcinoma Carrier Proteins Signal Transduction |
| Zdroj: | Oncogene. 38(15) |
| ISSN: | 1476-5594 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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