TRIM56 Suppresses Multiple Myeloma Progression by Activating TLR3/TRIF Signaling

Chen, Ying; Zhao, Jing; Li, Dengzhe; Hao, Jinxia; He, Pengcheng; Wang, Huaiyu; Zhang, Mei

doi:10.3349/ymj.2018.59.1.43

Cited by 21 publications

(16 citation statements)

References 32 publications

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“…Besides, TRIM56 is inducible by virus or IFN-beta and is essential for TLR3 signaling in response to virus infection 19 . However, the detailed role of TRIM56 in cancer progression is still not clear, although some studies showed TRIM56 could suppress malignancy progression in ovary cancer and multiple myeloma 32,33 . In our study, we identify that TRIM56 exerts its stabilization effect on ER alpha protein, which is dependent on both the RING domain at the N-terminal and the WD40 domain at the C-terminal.…”

Section: Discussionmentioning

confidence: 99%

Regulation of estrogen signaling and breast cancer proliferation by an ubiquitin ligase TRIM56

Xue

Zhang

et al. 2019

Oncogenesis

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Breast cancer ranks no. 1 in women cancer worldwide, while 60–70% are estrogen receptor alpha positive. The estrogen selective modulators, such as tamoxifen, become the effective drugs for controlling ER alpha breast cancer progression. However, tamoxifen resistance will develop during long-time treatment and cancer progression. Thus, further understanding of ER alpha signaling becomes necessary for the improvement of breast cancer therapy. Here, we identify TRIM56 as a novel regulatory factor in ER alpha signaling. TRIM56 expression is positively correlated with ER alpha and PR in breast cancer samples and is related to poor prognosis in endocrine therapy patients. TRIM56 depletion significantly decreases ER alpha signaling activity and ER-alpha-positive breast cancer proliferation in vitro and in vivo. TRIM56 associates with AF1 domain of ER alpha via its WD40 domain in the cytoplasm. TRIM56 prolongs ER alpha protein stability, possibly through targeting ER alpha K63-linked ubiquitination. In conclusion, our study reveals an interesting posttranslational mechanism between TRIM56 and ER alpha in breast cancer progression. Targeting TRIM56 could be a promising approach for ER-alpha-positive breast cancer.

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Section: Discussionmentioning

confidence: 99%

Regulation of estrogen signaling and breast cancer proliferation by an ubiquitin ligase TRIM56

Xue

Zhang

et al. 2019

Oncogenesis

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“…To further explore the molecular mechanism of miR‐9 exerting its function on MM cell lines, the online software miRcode (http://www.mircode.org/) was used to predict the potential endogenous targets of miR‐9. Among the potential targets, TRIM56 was chosen for further study because it was implicated in a series of biological processes and also demonstrated to play an important role in MM pathogenesis (Chen et al, ). Given the hypothesis that TRIM56 might be a target of miR‐9, we observed whether the 3′‐UTR of TRIM56 was regulated by miR‐9 in MM cells by luciferase reporter assay.…”

Section: Resultsmentioning

confidence: 99%

“…A recent document reported that the dysregulation of TRIM family proteins played a critical role in cell carcinogenesis, leading to multiple human cancers (Hatakeyama, ). Moreover, TRIM56 level was found to be downregulated in MM cells, and TRIM56 repressed the progression of MM by TLR3/TRIF signaling pathway, indicating its role as a tumor suppressor in MM (Chen et al, ). In this study, we validated that miR‐9 inhibited TRIM56 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Tripartite motif‐containing protein 56 (TRIM56) has been demonstrated to implicate in many types of fundamental processes (Tsuchida et al, ). Moreover, TRIM56 plays a critical role in MM pathogenesis (Chen et al, ). It was reported that TRIM56 was an essential component of the Toll‐like receptor 3 (TLR3) signaling pathway, and TLR3 ligands triggered the apoptosis in MM cells (Chiron et al, ; Shen et al, ).…”

Section: Introductionmentioning

confidence: 99%

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MiR‐9 promotes multiple myeloma progression by regulating TRIM56/NF‐κB pathway

Huang

Liu

Zhao

et al. 2019

Cell Biology International

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miR-9 has been reported to play a pivotal role in multiple human cancers by acting as an oncogene or tumor suppressor. In this study, we explored the possible role and molecular mechanism of miR-9 in multiple myeloma (MM). The miR-9 expression was examined by quantitative real-time polymerase chain reaction assay. Transfection with miR-9-mimics, miR-9-inhibitor, pcDNA-TRIM56, or si-TRIM56 into cells was used to change the expression levels of miR-9 and TRIM56. Western blot analysis was used to detect the expression of TRIM56, p65, p-p65, IκBα, and p-IκBα. The potential target of miR-9 was confirmed by luciferase reporter assay. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay, colony formation assay, and flow cytometry were used to assess the abilities of cell proliferation and apoptosis. miR-9 was upregulated in MM patients and cell lines, and miR-9 overexpression promoted proliferation and repressed apoptosis in MM cell lines. TRIM56 was confirmed as a target of miR-9. Moreover, TRIM56 reversed miR-9-mediated pro-proliferation and anti-apoptosis effect on MM cell lines. Furthermore, nuclear factor-κB (NF-κB) pathway was involved in miR-9/TRIM56-mediated regulation on MM cell lines. miR-9 promoted the development and progression of MM by regulating TRIM56/NF-κB pathway, thereby providing a potential microRNA-based target for MM therapy.

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“…TNS1 was rarely reported to be associated with cancer, but was identified as a potential biomarker in human colorectal cancer [23] and a regulator of metastatic potential in colorectal cancer via altering expression of genes involved in cell motility [24]. In contrast, previous studies [28, 29] have identified TRIM56 as a tumor suppressor through activation of TLR3/TRIF signaling pathway, which was consistent with the result that TRIM56 expression was a favorable indicator of MIBC in this study. Utilizing the expression profiles of these three signatures, we successfully built a multivariable Cox regression model to calculate risk scores and stratified the MIBC patients into high and low risk groups.…”

Section: Discussionmentioning

confidence: 99%

Systematic analysis of gene expression profiles reveals prognostic stratification and underlying mechanisms for muscle-invasive bladder cancer

Zhang

Huang

et al. 2019

Cancer Cell Int

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BackgroundMuscle-invasive bladder cancer (MIBC) is originated in the muscle wall of the bladder, and is the ninth most common malignancy worldwide. However, there are no reliable, accurate and robust gene signatures for MIBC prognosis prediction, which is of the importance in assisting oncologists to make a more accurate evaluation in clinical practice.MethodsThis study used univariable and multivariable Cox regression models to select gene signatures and build risk prediction model, respectively. The t-test and fold change methods were used to perform the differential expression analysis. The hypergeometric test was used to test the enrichment of the differentially expressed genes in GO terms or KEGG pathways.ResultsIn the present study, we identified three prognostic genes, KLK6, TNS1, and TRIM56, as the best subset of genes for muscle-invasive bladder cancer (MIBC) risk prediction. The validation of this stratification method on two datasets demonstrated that the stratified patients exhibited significant difference in overall survival, and our stratification was superior to three other stratifications. Consistently, the high-risk group exhibited worse prognosis than low-risk group in samples with and without lymph node metastasis, distant metastasis, and radiation treatment. Moreover, the upregulated genes in high-risk MIBC were significantly enriched in several cancer-related pathways. Notably, PDGFRB, a receptor for platelet-derived growth factor of PI3K-Akt signaling pathway, and TUBA1A were identified as two targets of multiple drugs. In addition, the angiogenesis-related genes, as well as two marker genes of M2 macrophage, CD163 and MRC1, were highly upregulated in high-risk MIBC.ConclusionsIn summary, this study investigated the underlying molecular mechanism and potential therapeutic targets associated with worse prognosis of high-risk MIBC, which could improve our understanding of progression of MIBC and provide new therapeutic strategies for the MIBC patients.

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TRIM56 Suppresses Multiple Myeloma Progression by Activating TLR3/TRIF Signaling

Cited by 21 publications

References 32 publications

Regulation of estrogen signaling and breast cancer proliferation by an ubiquitin ligase TRIM56

Regulation of estrogen signaling and breast cancer proliferation by an ubiquitin ligase TRIM56

MiR‐9 promotes multiple myeloma progression by regulating TRIM56/NF‐κB pathway

Systematic analysis of gene expression profiles reveals prognostic stratification and underlying mechanisms for muscle-invasive bladder cancer

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