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Targeting TRIM3 Deletion-Induced Tumor-Associated Lymphangiogenesis Prohibits Lymphatic Metastasis in Esophageal Squamous Cell Carcinoma

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Targeting TRIM3 Deletion-Induced Tumor-Associated Lymphangiogenesis Prohibits Lymphatic Metastasis in Esophageal Squamous Cell Carcinoma Oncogene https://doi.org/10.1038/s41388-018-0621-5 ARTICLE Targeting TRIM3 deletion-induced tumor-associated lymphangiogenesis prohibits lymphatic metastasis in esophageal squamous cell carcinoma 1,2 1,3 4 1 2 1 1 1 Jinrong Zhu ● Geyan Wu ● Zunfu Ke ● Lixue Cao ● Miaoling Tang ● Ziwen Li ● Qiaojia Li ● Junhao Zhou ● 1 3 1,2 Zhanyao Tan ● Libing Song ● Jun Li Received: 23 July 2018 / Accepted: 23 November 2018 © Springer Nature Limited 2018 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 1234567890();,: 1234567890();,: 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. Introduction The significant contribution of tumor-associated lym- phangiogenesis to lymph node (LN) metastasis and distant metastasis, which results in poor prognosis of cancer These authors contributed equally: Jinrong Zhu, Geyan Wu, Zunfu Ke patients with lymphatic metastasis, has attracted increasing – Supplementary information The online version of this article (https:// attention over the last few decades [1 3]. For instance, the doi.org/10.1038/s41388-018-0621-5) contains supplementary 5-year overall survival rate inpatients with esophageal material, which is available to authorized users. squamous cell carcinoma (ESCC) with lymphatic metastasis is only 10–15%, and the median survival time is less than 1 * Jun Li [email protected] year. In addition, patients with ESCC develop lymphatic metastasis at an early stage. LN metastasis has been iden- 1 Key Laboratory of Liver Disease of Guangdong Province, The tified as the most important predictor of prognosis in ESCC fi Third Af liated Hospital, Sun Yat-sen University, Guangzhou, [4–6]. Many studies have demonstrated that tumor- Guangdong, China associated lymphangiogenesis and lymphatic metastasis in 2 Department of biochemistry, Zhongshan School of medicine, Sun a variety of malignancies were largely attributed to upre- Yat-sen University, Guangzhou, Guangdong, China gulated vascular endothelial growth factor C (VEGF-C) [7– 3 State Key Laboratory of Oncology in South China, Cancer Center, 10]. A VEGF-C monoclonal antibody (VGX-100) was Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China examined in a clinical trial for malignant tumors that were 4 fi refractory to standard therapy. However, treatment with the Department of Pathology, The First Af liated Hospital, Sun Yat- VEGFC sen University, Guangzhou, Guangzhou, Guangdong 510060, VEGF-C monoclonal antibody or silencing of only China elicited a 60–70% reduction in lymphatic metastasis [11, J. Zhu et al. 12]. Therefore, the identification of novel therapeutic target fluorescence in situ hybridization (FISH) analysis of our (s) to inhibit tumor-associated lymphangiogenesis might collected ESCC specimens (n = 308) and by analysis of The represent a more effective strategy for the clinical inter- Cancer Genome Atlas (TCGA)-ESCC data set (n = 77) vention in cancer lymphatic metastasis. using GISTIC 2.0 (Genomic Identification of Significant Previous studies suggested that nuclear factor kappa B Targets in Cancer). Similar to the TCGA data set analysis (NF-κB) is abnormally activated in ESCC, and plays vital (38.59%), the FISH analysis revealed 36.04% heterozygous roles in lymphangiogenesis and lymphatic metastasis [13, TRIM3 deletions in our ESCC specimens (Fig. 1a and 14]. Approaches that terminate the hyperactivation of NF- Supplementary Figure S1a). Interestingly, an immunohis- κB have long been investigated as potential treatments for tochemical assay revealed that the TRIM3 protein was cancer [15, 16]. However, long-term treatment with most strongly expressed in normal esophageal tissues; however, NF-κB inhibitors leads to broad suppression of innate its level was noticeably lower in TRIM3-nondeleted ESCC, immunity [15, 16]. The anti-inflammatory drug, Tecfidera, and was further substantially reduced in TRIM3-deleted approved for the treatment of multiple sclerosis in the ESCC tissues (Fig. 1a, b). Concordantly, analyses of 15 United States and the European Union, exhibits immune- freshly collected clinical ESCC tissues and the TCGA- modulatory properties [17]. A Tecfidera-mediated NF-κB ESCC data set revealed that TRIM3 mRNA expression in inhibitory effect was attributed to reduction of the DNA- TRIM3-deleted ESCC was lower than that in TRIM3-non- binding activity and nuclear translocation of NF-κB[18– deleted ESCC (Supplementary Figure S1b and c). These 20]. However, the inhibitory effect of Tecfidera on cancer results suggested that genetic deletion represents a major lymphatic metastasis is unknown. mechanism of TRIM3 protein reduction in ESCC. Tripartite motif-containing 3 (TRIM3), also named Consistent with the results obtained from both our col- brain-expressed RING finger protein (BERP) or E3 ligase lected ESCC specimens and the TCGA-ESCC data set, RNF22, belongs to the RING finger-B-box-coiled coil patients with TRIM3-deleted ESCC had a significantly (RBCC) subgroup of RING finger proteins [21–23]. TRIM3 shorter overall and relapse-free survival compared with was originally identified as a protein from the cytoskeleton- those without TRIM3-deletion. We found that the TRIM3 associated recycling or transport complex that is involved in protein-lower cohort had shorter overall and relapse-free receptor recycling [22, 23]. Furthermore, loss of TRIM3 survival compared with the TRIM3 protein-higher cohort contributes to hippocampal plasticity and brain tumorigen- (Fig. 1c and Supplementary Figure S1d and e). Statistical esis, which is dependent on its E3 ligase activity [23, 24]. analysis showed that TRIM3 levels inversely correlated However, the precise molecular mechanism and clinical with clinical stage and tumor-node-metastasis (TNM) clas- significance of TRIM3 remains unclear. sification (Supplementary Table S2). Multiple clin- In the present study, we reported that loss of TRIM3 in icopathological variables, such as gender, age, T ESCC prolonged NF-κB activation via promotion of classification, clinical stage, N classification, M classifica- nuclear accumulation and transcriptional activity of NF-κB, tion, and copy number and expression of TRIM3, were which promoted ESCC lymphatic metastasis. Importantly, included for univariate and multivariate Cox regression treatment with Tecfidera inhibited the TRIM3 deletion- analysis, which showed that TRIM3 expression was an induced NF-κB constitutive activation, resulting in con- independent prognostic factor for survival outcome of siderable inhibition of lymphangiogenesis and LN patients with ESCC (P < 0.001; Supplementary Table S3). metastasis in ESCC. These findings demonstrated that het- The above data demonstrated that heterozygous deletion- erozygous deletion of TRIM3-sustained NF-κB signaling is mediated TRIM3 reduction was associated with ESCC a candidate driver of lymphatic metastasis in ESCC and progression. suggested that Tecfidera has therapeutic value to treat ESCC lymphatic metastasis. TRIM3 reduction correlates with lymphatic metastasis and microlymphatic vessel density Results Lymphatic metastasis and lymphangiogenesis have been identified as predictors of prognosis in ESCC [4–6]. Strik- Heterozygous deletion-mediated TRIM3 reduction ingly, we observed that TRIM3 reduction was not only correlates with poor prognosis in ESCC significantly associated with lymphatic metastasis (P < 0.001; Fig. 1d), but also correlated with microlymphatic The TRIM3 gene is located on chromosome 11p15, which vessel density (MLD) in both intratumoral and peritumoral frequently undergoes a loss of heterozygosity in human tissues (P < 0.01; P < 0.001) (Fig. 1e and Supplementary tumors, including ESCC [25, 26]. We examined the dele- Table S2), which suggested that TRIM3 reduction probably tion frequency of the TRIM3 gene by performing results in lymphangiogenesis and LN metastasis in ESCC. Targeting TRIM3 deletion-induced tumor-associated lymphangiogenesis prohibits lymphatic metastasis in. Fig. 1 Heterozygous deletion of TRIM3 correlates with poor prognosis TRIM3 (n = 308). d Left panel: two representative cases are shown. in human ESCC. a, b Representative FISH and IHC images (a) and Right panel: percentages of ESCC specimens showing low- or high- quantification of heterozygous TRIM3 deletions and TRIM3 expres- TRIM3 expression
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