Search

Tumor-associated macrophages play a crucial role in the tumor microenvironment. Tripartite motif 59 (TRIM59), a member of the tripartite motif (TRIM) family, is known to be associated with immunological diseases and macrophage activation. The functional and molecular mechanisms by which TRIM59 affects the occurrence and development of colorectal cancer (CRC) through macrophages are still not well understood. To address this, we generated macrophage-specific TRIM59 conditional knockout mice and utilized these mice to establish colitis-associated cancer and MC38 transplanted CRC models for further investigation. We found that the deficiency of TRIM59 in macrophages inhibited colorectal tumorigenesis in mice. This tumor-suppressive effect was achieved by promoting the activation of M1 macrophages via STAT1 signaling pathway. Further mechanistic studies revealed that TRIM59 could regulate macrophage polarization by ubiquitinating and degrading STAT1. These findings provide evidence that TRIM59 deficiency promotes M1 macrophage activation and inhibits CRC through the STAT1 signaling pathway, suggesting that the TRIM59/STAT1 signaling pathway may be a promising target for CRC. [ABSTRACT FROM AUTHOR]

Background: Tripartite motif containing 59 (TRIM59) is a ubiquitin ligase and is involved in the pathogenesis of various diseases, including cancers, sepsis, and other immune-related diseases. However, it has not been defined whether TRIM59 plays a role in ischemic stroke in mice. Methods: This study determined the influence of Trim59 deficiency on experimental stroke outcomes and the cerebral proteomic profile using myeloid cell Trim59 conditional knockout (Trim59-cKO) mice and a label-free quantitative proteomic profiling technique. The possible mechanisms by which TRIM59 affected stroke onset were elucidated by in vivo and in vitro experiments. Results: Immunofluorescence staining results showed that TRIM59 expression was up-regulated after cerebral ischemia and co-localized with macrophages. Myeloid cell Trim59 deficiency exacerbated ischemic injury on day 3 after experimental stroke. In proteomic analysis, 23 differentially expressed proteins were identified in ischemic brain of Trim59-cKO mice as compared to Trim59flox/flox mice. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the differentially expressed proteins were enriched in complement and coagulation cascades. Protein–protein interaction analysis suggested the central role of clusterin in the interaction network. ELISA and Western blot assays confirmed the reduced levels of clusterin protein in the ischemic brains of Trim59-cKO mice. Further experimental results showed that clusterin was expressed in neurons. Conditional co-culture experiments of primary neurons and bone marrow-derived macrophages demonstrated that LPS stimulated macrophages to secrete complement C3. In addition, TRIM59 may affect the changes in clusterin expression in an indirect manner by influencing the secretion of complement C3 in macrophages. In vivo experiments also proved a significant increase in C3 levels in the brains of Trim59-cKO mice after ischemia. Conclusion: Myeloid cell Trim59 deficiency aggravated ischemic stroke outcomes in conjunction with a distinct cerebral proteomic profile, and the underlying mechanism may be related to the regulation of macrophage C3 expression by TRIM59. [ABSTRACT FROM AUTHOR]

Abstract Tumor-associated macrophages play a crucial role in the tumor microenvironment. Tripartite motif 59 (TRIM59), a member of the tripartite motif (TRIM) family, is known to be associated with immunological diseases and macrophage activation. The functional and molecular mechanisms by which TRIM59 affects the occurrence and development of colorectal cancer (CRC) through macrophages are still not well understood. To address this, we generated macrophage-specific TRIM59 conditional knockout mice and utilized these mice to establish colitis-associated cancer and MC38 transplanted CRC models for further investigation. We found that the deficiency of TRIM59 in macrophages inhibited colorectal tumorigenesis in mice. This tumor-suppressive effect was achieved by promoting the activation of M1 macrophages via STAT1 signaling pathway. Further mechanistic studies revealed that TRIM59 could regulate macrophage polarization by ubiquitinating and degrading STAT1. These findings provide evidence that TRIM59 deficiency promotes M1 macrophage activation and inhibits CRC through the STAT1 signaling pathway, suggesting that the TRIM59/STAT1 signaling pathway may be a promising target for CRC.

Tripartite motif-containing protein 59 (TRIM59) is a biomarker for multiple tumors with crucial roles. However, the specific role of TRIM59 in germ cells remains largely unknown. Here, we investigated the effects and underlying regulatory mechanisms of TRIM59 on germ cells using the mouse spermatogonial cell line GC-1. Our results demonstrated that TRIM59 promoted proliferation and inhibited apoptosis of GC-1 cells. Mechanistically, TRIM59 maintained GC-1 cell behaviors through ubiquitination of AXIN1 to activate β-catenin signaling. Furthermore, activation of β-catenin signaling reversed the effects mediated by Trim59 knockdown in GC-1 cells. Collectively, our study revealed a major role and regulatory mechanism of TRIM59 in GC-1 cells, which sheds new light on the molecular pathogenesis of defects in spermatogenesis and may provide therapeutic targets for treatment of male infertility.

This study examines the involvement of TRIM59 in silica-induced pulmonary fibrosis and explores the therapeutic efficacy of Tanshinone IIA (Tan IIA). In vivo experiments conducted on rats with silica-induced pulmonary fibrosis unveiled an increase in TRIM59 levels and a decrease in PPM1A levels. Subsequent investigations using in vitro silicosis cell models demonstrated that modulation of TRIM59 expression significantly impacts silicosis fibrosis, influencing the levels of PPM1A and activation of the Smad2/3 signaling pathway. Immunofluorescence and co-immunoprecipitation assays confirmed the interaction between TRIM59 and PPM1A in fibroblasts, wherein TRIM59 facilitated the degradation of PPM1A protein via proteasomal and ubiquitin-mediated pathways. Furthermore, employing a rat model of silica-induced pulmonary fibrosis, Tan IIA exhibited efficacy in mitigating lung tissue damage and fibrosis. Immunohistochemical analysis validated the upregulation of TRIM59 and downregulation of PPM1A in silica-induced pulmonary fibrosis, which Tan IIA alleviated. In vitro studies elucidated the mechanism by which Tan IIA regulates the Smad2/3 signaling pathway through TRIM59-mediated modulation of PPM1A. Treatment with Tan IIA in silica-induced fibrosis cell models resulted in concentration-dependent reductions in fibrotic markers and attenuation of relevant protein expressions. Tan IIA intervention in silica-induced fibrosis cell models mitigated the TRIM59-induced upregulation of fibrotic markers and enhanced PPM1A expression, thereby partially reversing Smad2/3 activation. Overall, the findings indicate that while overexpression of TRIM59 may activate the Smads pathway by suppressing PPM1A expression, treatment with Tan IIA holds promise in counteracting these effects by inhibiting TRIM59 expression.

Abstract Background Pulmonary hypertension (PH), an infrequent disease, is characterized by excessive pulmonary vascular remodeling and proliferation of pulmonary artery smooth muscle cells (PASMCs). However, its underlying molecular mechanisms remain unclear. Uncovering its molecular mechanisms will be beneficial to the treatment of PH. Methods Differently expressed genes (DEGs) in the lung tissues of PH patients were analyzed with a GEO dataset GSE113439. From these DEGs, we focused on TRIM59 which was highly expressed in PH patients. Subsequently, the expression of TRIM59 in the pulmonary arteries of PH patients, lung tissues of PH rat model and PASMCs cultured in a hypoxic condition was verified by quantitative real-time PCR (qPCR), western blot and immunohistochemistry. Furthermore, the role of TRIM59 in PAMSC proliferation and pathological changes in PH rats was assessed via gain-of-function and loss-of-function experiments. In addition, the transcriptional regulation of YAP1/TEAD4 on TRIM59 was confirmed by qPCR, western blot, luciferase reporter assay, ChIP and DNA pull-down. In order to uncover the underlying mechanisms of TRIM59, a protein ubiquitomics and a CoIP- HPLC–MS/MS were companied to identify the direct targets of TRIM59. Results TRIM59 was highly expressed in the pulmonary arteries of PH patients and lung tissues of PH rats. Over-expression of TRIM59 accelerated the proliferation of PASMCs, while TRIM59 silencing resulted in the opposite results. Moreover, TRIM59 silencing mitigated the injuries in heart and lung and attenuated pulmonary vascular remodeling during PH. In addition, its transcription was positively regulated by YAP1/TEAD4. Then we further explored the underlying mechanisms of TRIM59 and found that TRIM59 overexpression resulted in an altered ubiquitylation of proteins. Accompanied with the results of CoIP- HPLC–MS/MS, 34 proteins were identified as the direct targets of TRIM59. Conclusion TRIM59 was highly expressed in PH patients and promoted the proliferation of PASMCs and pulmonary vascular remodeling, thus contributing to the pathogenesis of PH. It is indicated that TRIM59 may become a potential target for PH treatment.

Increasing evidence suggests that circular RNA (circRNA) plays an important role in non‐small cell lung cancer (NSCLC) progression. This study aimed to investigate the role and potential molecular mechanism of circ_0006324 in NSCLC. The expression levels of circ_0006324, miR‐496, miR‐488‐5p, and tripartite motif‐containing 59 (TRIM59) mRNA were determined by quantitative real‐time polymerase chain reaction (PCR). 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide assay, EdU assay, and flow cytometry were carried out to evaluate cell proliferation and apoptosis. The extracellular acidification rate and lactic acid production were examined to assess cell glycolysis. Western blot assay was used to detect protein levels. The target relationship of circ_0006324/miR‐496/TRIM59 axis was validated by RNA pull‐down assay, dual luciferase reporter assay, and radio immunoprecipitation assay. Xenograft tumor assay was performed to reveal the function of circ_0006324 in vivo. Circ_0006324 was upregulated in NSCLC and related to tumor node metastasis stage and distant metastasis. Knockdown of circ_00006324 impeded NSCLC cell proliferation, glycolysis, and promoted cell apoptosis. MiR‐496 was verified as a target of circ_0006324 and circ_00006324 mediated the altering of cell proliferation, apoptosis, and glycolysis of NSCLC cells through targeting miR‐496. TRIM59 was verified as a target of miR‐496, and circ_0006324 positively regulated TRIM59 expression by targeting miR‐496. Overexpression of TRIM59 could reverse the effects of circ_0006324 silencing on the proliferation, apoptosis, and glycolysis of NSCLC cells. Circ_0006324 knockdown impeded NSCLC tumor growth in vivo. Circ_0006324 functioned as a tumor promoter in NSCLC to promote cell proliferation, cell cycle progression, and glycolysis and inhibit cell apoptosis via miR‐496/TRIM59 axis. Highlights: Circ_0006324 promotes non‐small cell lung cancer (NSCLC) progression.Circ_0006324 sponges miR‐496.TRIM59 is a target of miR‐496. [ABSTRACT FROM AUTHOR]

Neuroblastoma, predominantly afflicting young individuals, is characterized as an embryonal tumor, with poor prognosis primarily attributed to chemoresistance. This study delved into the impact of tripartite motif (TRIM) 59, an E3 ligase, on neuroblastoma development and chemosensitivity through mediating ferroptosis and the involvement of the tumor suppressor p53. Clinical samples were assessed for TRIM59 and p53 levels to explore their correlation with neuroblastoma differentiation. In neuroblastoma cells, modulation of TRIM59 expression, either through overexpression or knockdown, was coupled with doxorubicin hydrochloride (DOX) or ferrostatin-1 (Fer-1) therapy. In vivo assessments examined the influence of TRIM59 knockdown on neuroblastoma chemosensitivity to DOX. Co-immunoprecipitation and ubiquitination assays investigated the association between TRIM59 and p53. Proliferation was gauged with Cell Counting Kit-8, lipid reactive oxygen species (ROS) were assessed via flow cytometry, and protein levels were determined by Western blotting. TRIM59 expression was inversely correlated with neuroblastoma differentiation and positively linked to cell proliferation in response to DOX. Moreover, TRIM59 impeded lipid ROS generation and ferroptosis by directly interacting with p53, promoting its ubiquitination and degradation in DOX-exposed neuroblastoma cells. Fer-1 countered the impact of TRIM59 knockdown on neuroblastoma, while TRIM59 knockdown enhanced the therapeutic efficacy of DOX in xenograph mice. This study underscores TRIM59 as an oncogene in neuroblastoma, fostering growth and chemoresistance by suppressing ferroptosis through p53 ubiquitination and degradation. TRIM59 emerges as a potential strategy for neuroblastoma therapy.

Background: Pulmonary hypertension (PH), an infrequent disease, is characterized by excessive pulmonary vascular remodeling and proliferation of pulmonary artery smooth muscle cells (PASMCs). However, its underlying molecular mechanisms remain unclear. Uncovering its molecular mechanisms will be beneficial to the treatment of PH. Methods: Differently expressed genes (DEGs) in the lung tissues of PH patients were analyzed with a GEO dataset GSE113439. From these DEGs, we focused on TRIM59 which was highly expressed in PH patients. Subsequently, the expression of TRIM59 in the pulmonary arteries of PH patients, lung tissues of PH rat model and PASMCs cultured in a hypoxic condition was verified by quantitative real-time PCR (qPCR), western blot and immunohistochemistry. Furthermore, the role of TRIM59 in PAMSC proliferation and pathological changes in PH rats was assessed via gain-of-function and loss-of-function experiments. In addition, the transcriptional regulation of YAP1/TEAD4 on TRIM59 was confirmed by qPCR, western blot, luciferase reporter assay, ChIP and DNA pull-down. In order to uncover the underlying mechanisms of TRIM59, a protein ubiquitomics and a CoIP- HPLC–MS/MS were companied to identify the direct targets of TRIM59. Results: TRIM59 was highly expressed in the pulmonary arteries of PH patients and lung tissues of PH rats. Over-expression of TRIM59 accelerated the proliferation of PASMCs, while TRIM59 silencing resulted in the opposite results. Moreover, TRIM59 silencing mitigated the injuries in heart and lung and attenuated pulmonary vascular remodeling during PH. In addition, its transcription was positively regulated by YAP1/TEAD4. Then we further explored the underlying mechanisms of TRIM59 and found that TRIM59 overexpression resulted in an altered ubiquitylation of proteins. Accompanied with the results of CoIP- HPLC–MS/MS, 34 proteins were identified as the direct targets of TRIM59. Conclusion: TRIM59 was highly expressed in PH patients and promoted the proliferation of PASMCs and pulmonary vascular remodeling, thus contributing to the pathogenesis of PH. It is indicated that TRIM59 may become a potential target for PH treatment. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease around the world. However, no specific medicine has been approved for NAFLD treatment. Our study was conducted to explore the role and mechanism of TRIM59 in NAFLD, aiming to provide a novel target for NAFLD treatment. Here, the expression of TRIM family members was detected in 10 mild and severe NAFLD tissues as well as 10 normal tissues. TRIM59 expression was verified in 10 normal tissues and 25 mild and severe NAFLD tissues. Palmitic acid and high-fatty diet were used for the construction of NAFLD models. Oil Red O staining was used to detect the level of steatosis. The content of TNF-α, IL-6, and IL-8 was measured to reflect the level of inflammation. Lipid reactive oxygen species was estimated by flow cytometry. We found that TRIM59 was highly expressed in NAFLD tissues compared with normal liver tissues. The inhibition of TRIM59 could inhibit the steatosis and inflammation in NAFLD, whereas its overexpression exhibited reversed effects. The application of ferroptosis inhibitor, deferoxamine, could markedly ameliorate steatosis and inflammation, which was mediated by overexpressed TRIM59. Besides, TRIM59 was demonstrated to interact with GPX4 and promoted its ubiquitination. The overexpression of GPX4 could significantly reverse the pathogenic effects of TRIM59 in NAFLD. Additionally, the inhibition of TRIM59 appeared to be a promising strategy to ameliorate NAFLD in mice model. In summary, our study revealed that TRIM59 could promote steatosis and ferroptosis in NAFLD via enhancing GPX4 ubiquitination. TRIM59 could be a potential target for NAFLD treatment. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) is a critical organelle that preserves the protein homeostasis of cells. Under various stress conditions, cells evolve a degree of capacity to maintain ER proteostasis, which is usually augmented in tumor cells, including colorectal cancer (CRC) cells, to bolster their survival and resistance to apoptosis. Bortezomib (BTZ) is a promising drug used in CRC treatment; however, its main limitation result from drug resistance. Here, we identified the role of tripartite motif-containing protein 59 (TRIM59)–a protein localized on the ER membrane– in the prevention of BTZ-mediated CRC killing. Depletion of TRIM59 is associated with the enhancement of ER stress and a remarkable increase in unfolded protein response (UPR) signaling. Besides, TRIM59 strengthens ER-associated degradation (ERAD) and alleviates the generation of ROS. Of note, TRIM59 knockdown synergizes with the anti-cancer effect of BTZ both in vitro and in vivo. Our findings revealed a role for TRIM59 in the ER by guarding ER proteostasis and represents a novel therapeutic target of CRC. [ABSTRACT FROM AUTHOR]

The tripartite motif (TRIM) proteins play critical roles in viral infection by modulating innate immunity. However, the molecular and antiviral activity of TRIM59 in mandrain fish is not fully understood. In present study, we cloned and sequenced the TRIM59 core sequence and explored its characteristics in Mandarin fish. The Siniperca chuatsi TRIM59 (scTRIM59) showed relatively high expression in immune-related organs. scTRIM59 expression was significantly down-regulated post ISKNV infection in vivo and vitro, but up-regulated at the early stages of SCRV infection in CPB cells. The overexpression of scTRIM59 inhibited ISKNV and SCRV infection, but decreased the expression of IRF3/IRF7-mediated signal genes. However, knockdown of scTRIM59 promoted the ISKNV and SCRV infection, but increased the expression of IRF3/IRF7-mediated signal genes. Those results indicated that scTRIM59 negatively regulated ISKNV, SCRV infection and IRF3/IRF7-mediated signal genes. This study provided new ideas about the function of scTRIM59. • scTRIM59 was widely expressed in the tissues of mandarin fish, especially in immune organs. • scTRIM59 expression was down-regulated post ISKNV infection, however, scTRIM59 was up-regulated post SCRV infection. • scTRIM59 negatively regulated ISKNV, SCRV infection and IRF3/IRF7-mediated signal genes. [ABSTRACT FROM AUTHOR]

This study examines the involvement of TRIM59 in silica-induced pulmonary fibrosis and explores the therapeutic efficacy of Tanshinone IIA (Tan IIA). In vivo experiments conducted on rats with silica-induced pulmonary fibrosis unveiled an increase in TRIM59 levels and a decrease in PPM1A levels. Subsequent investigations using in vitro silicosis cell models demonstrated that modulation of TRIM59 expression significantly impacts silicosis fibrosis, influencing the levels of PPM1A and activation of the Smad2/3 signaling pathway. Immunofluorescence and co-immunoprecipitation assays confirmed the interaction between TRIM59 and PPM1A in fibroblasts, wherein TRIM59 facilitated the degradation of PPM1A protein via proteasomal and ubiquitin-mediated pathways. Furthermore, employing a rat model of silica-induced pulmonary fibrosis, Tan IIA exhibited efficacy in mitigating lung tissue damage and fibrosis. Immunohistochemical analysis validated the upregulation of TRIM59 and downregulation of PPM1A in silica-induced pulmonary fibrosis, which Tan IIA alleviated. In vitro studies elucidated the mechanism by which Tan IIA regulates the Smad2/3 signaling pathway through TRIM59-mediated modulation of PPM1A. Treatment with Tan IIA in silica-induced fibrosis cell models resulted in concentration-dependent reductions in fibrotic markers and attenuation of relevant protein expressions. Tan IIA intervention in silica-induced fibrosis cell models mitigated the TRIM59-induced upregulation of fibrotic markers and enhanced PPM1A expression, thereby partially reversing Smad2/3 activation. Overall, the findings indicate that while overexpression of TRIM59 may activate the Smads pathway by suppressing PPM1A expression, treatment with Tan IIA holds promise in counteracting these effects by inhibiting TRIM59 expression. [Display omitted] • TRIM59 is up-regulated in silicotic rat lung tissues, with down-regulated of PPM1A. • TRIM59 affects silicosis fibrosis, PPM1A expression and Smads pathway activation. • TRIM59 promotes the degradation of PPM1A through proteasomes and ubiquitination. • Tan IIA can inhibit silicosis fibrosis and TRIM59 expression in vivo and in vitro. • Tan IIA mediates TRIM59 to modulate PPM1A for Inhibition of Smads pathway activation. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Cancer Biotherapy is the property of Editorial Office of Chinese Journal of Cancer Biotherapy and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Colorectal cancer (CRC) is the second leading cause of cancer‐related mortality in developing countries. Tripartite motif‐59 (TRIM59) a member of the TRIM ubiquitin ligase family, is a surface molecule that regulates biological processes such as cell proliferation, apoptosis, and tumorigenesis. Previous studies reported that TRIM59 expression was upregulated in human CRC, however, the expression pattern and role of TRIM59 in benign colorectal lesions remain unclear. Sixty patients diagnosed with CRC and 60 patients with benign lesions (Crohn's disease, ulcerative colitis, adenoma, and familial adenomatous polyposis) were recruited to the present study. TRIM59 gene expression was assessed by real‐time quantitative polymerase chain reaction. Expression of TRIM59 protein and p‐AKT were determined using, enzyme‐linked immunoassay while p53 expression was detected by immunohistochemistry. Antioxidant/oxidant role of glutathione (GSH)/malondialdehyde (MDA) were evaluated by colorimetric methods in all of the studied groups. Our results showed upregulated expressions of TRIM59 gene and protein levels in CRC tissues and benign colonic lesions compared to nontumor tissues. Their levels were higher in inflammatory compared to noninflammatory bowel lesions. There were significant interrelations among TRIM59 gene expression, protein levels, tumor, node, metastasis staging, and the presence of metastasis (p < 0.0001). Receiver–operator characteristic curve analyses showed that at the cutoff point of 2.5 TRIM59 mRNA expression can discriminate between CRC cases and benign bowel group (area under the curve [AUC]: 0.639, sensitivity: 86.7%, specificity: 41.7%), and between CRC and controls (AUC: 0.962, sensitivity: 90%, specificity: 91.7%). TRIM59 could be a potential biomarker in the early detection, diagnosis, and treatment of benign colonic lesions and CRC. [ABSTRACT FROM AUTHOR]

Tripartite motif-containing protein 59 (TRIM59) is a biomarker for multiple tumors with crucial roles. However, the specific role of TRIM59 in germ cells remains largely unknown. Here, we investigated the effects and underlying regulatory mechanisms of TRIM59 on germ cells using the mouse spermatogonial cell line GC-1. Our results demonstrated that TRIM59 promoted proliferation and inhibited apoptosis of GC-1 cells. Mechanistically, TRIM59 maintained GC-1 cell behaviors through ubiquitination of AXIN1 to activate β-catenin signaling. Furthermore, activation of β-catenin signaling reversed the effects mediated by Trim59 knockdown in GC-1 cells. Collectively, our study revealed a major role and regulatory mechanism of TRIM59 in GC-1 cells, which sheds new light on the molecular pathogenesis of defects in spermatogenesis and may provide therapeutic targets for treatment of male infertility., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Neuroblastoma (NB) is a childhood cancer that often occurs in the sympathetic nervous system. Previous reports showed that long non-coding RNAs (lncRNAs) could affect the progress of NB, but the mechanism is still indistinct. In this study, we unfolded the roles of LINC01296 in NB tissues and cells. The level of LINC01296, microRNA-584-5p (miR-584-5p), miR-34a-5p and mRNA of tripartite motif-containing 59 (TRIM59) were indicated by quantitative real-time polymerase chain reaction (qRT-PCR) in NB tissues. The capacities of NB cells were validated by MTT assay, Edu assay, transwell assay and flow cytometry analysis. The interplay between miR-584-5p/miR-34a-5p and LINC01296 or TRIM59 were detected by dual-luciferase reporter assay. Finally, the in vivo experiment was implemented to verify the effect of LINC01296 in vivo. The level of LINC01296 and TRIM59 were increased, whereas miR-584-5p and miR-34a-5p levels were reduced in NB tissues in contrast to that in normal tissues. For functional analysis, LINC01296 deficiency inhibited the cell vitality, cell proliferation, migration and invasion in NB cells, whereas promoted cell apoptosis. Moreover, miR-584-5p and miR-34a-5p were validated to act as a tumor repressive effect in NB cells by restraining TRIM59. The results also showed that LINC01296 could regulate the development of NB. In mechanism, LINC01296 acted as a miR-584-5p and miR-34a-5p sponge to modulate TRIM59 expression. In addition, LINC01296 knockdown also attenuated tumor growth in vivo. LINC01296 promotes the progression of NB by increasing TRIM59 expression via regulating miR-584-5p and miR-34a-5p, which also offered an underlying targeted therapy for NB treatment. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is a common, highly malignant bone tumor. Tripartite motif-containing protein 59 (TRIM59) has been identified as a potential oncogenic protein involved in the initiation and progression of various human carcinomas. Nonetheless, the possible roles and molecular mechanisms of action of TRIM59 in OS remain unclear. In this study, we found that TRIM59 expression levels were frequently upregulated in OS tissues and cell lines. TRIM59 knockdown significantly suppressed the proliferation, migration, and invasion of OS cells and promoted OS cell apoptosis, whereas TRIM59 overexpression had the opposite effects. In vivo experiments demonstrated that TRIM59 knockdown suppressed OS tumor growth and metastasis in vivo. Furthermore, we found that TRIM59 directly interacted with phospho-STAT3 in OS cells. The downregulation of STAT3 levels attenuated TRIM59-induced cell proliferation and invasion. Taken together, our results indicate that TRIM59 promoted OS progression via STAT3 activation. Therefore, our study may provide a novel therapeutic target for OS. [ABSTRACT FROM AUTHOR]

The stability of deoxyribonucleic acid (DNA) depends on several factors including temperature, humidity, and period conditions. Temperature plays an essential role in DNA degradation, the high relative humidity cause rapid decay of DNA. The aim of this study is to assess the effects of different conditions [Temperature (0°C and 55°C) and Humidity (58% and 12%)] on DNA methylation by bisulfite. The study has investigated 30 samples of blood that have been collected from healthy people. The samples were distributed for four groups each group has 15 samples were exposed at different conditions temperature (0°C, and 55°C) and humidity (58%, and 12%) in different time (0,1,2,4 and 8 days). The DNA methylation of TRIM 59 gene was stable in room temperature whereas in the 0°C and 55°C the results showed that a slight regression in TRIM59gene. [ABSTRACT FROM AUTHOR]

Abstract Background Exosomes are emerging as important mediators of the cross-talk between tumor cells and the microenvironment. The communication between tumor-derived exosomes and macrophages has a critical role in facilitating tumor progression. However, the mechanisms by which exosomes modulate tumor development in lung cancer are not fully understood. Methods Short hairpin RNA mediated knockdown or exogenous expression of TRIM59 combined with in vitro and in vivo assays were performed to prove the functional significance of TRIM59. Western blotting, real-time PCR, co-immunoprecipitation, immunofluorescence (IF) staining assays, proximity ligation assay (PLA), ubiquitination assays, lactate secretion and lipid droplets content measurement, and rescue experiments were used to evaluate the mechanism. Lewis lung carcinoma (LLC) cells were injected via subcutaneously or tail vein into C57BL/6 wild-type (WT) and transgenic mice to assess the role of TRIM59 in vivo. Results We demonstrated that tripartite motif-containing 59 (TRIM59) was expressed in lung cancer cells-derived exosomes, and can be transferred to macrophages through the exosomes. Activated macrophages by TRIM59 promote lung cancer progression in vitro and in vivo. Mechanistic investigations revealed that TRIM59 physically interacts with abhydrolase domain containing 5 (ABHD5) and directly induced the ubiquitination of ABHD5 and led to its proteasome-dependent degradation. ABHD5, an lipolytic co-activator, deficiency induced metabolic reprogramming and enabled NLRP3 inflammasome activation in macrophages. Further studies showed that the exacerbation of NLRP3 inflammasome activation by ABHD5 deficiency, provides a positive feedback loop to promote cancer progression by preferentially secrete the proinflammatory cytokine IL-1β. Conclusions Collectively, these data indicate that tumor-derived exosomal TRIM59 converts macrophages to tumor-promoting functions of macrophages via regulating ABHD5 proteasomal degradation, to activate NLRP3 inflammasome signaling pathway to promote lung cancer progression by IL-1β secretion. Our findings also indicate that tumor-derived exosomal TRIM59 has an important role in intercellular communication for fostering an inflammatory microenvironment and promoting lung metastasis.

microRNAs (miRNAs) are important in tumor suppression and oncogenesis. In this study, we aimed to explore the role of miR-4698 with its potential target, Tripartite motif-containing 59 (Trim59), a protein with oncogenic function, in hepatocellular carcinoma (HCC). The expression of miR-4698 was significantly lower in HCC tissues and HCC cell lines as compared to the levels expressed in normal tissues adjacent to tumors and in normal hepatic cell line. Overexpression of miR-4698 in HCC cells by transfection of its mimic significantly inhibited cell growth, migration, invasion and epithelial-mesenchymal transition (EMT), whereas, its antisense oligonucleotides (ASOs) exerted an opposite effect. Trim59 was identified as a target of miR-4698 in miRDB and consistent with this, the expression of Trim59 was inversely correlated with miR-4698 in HCC, and miR-4698 overexpression led to a significant decrease in luciferase activity of pRL-Trim59-3’-UTR, but not mutant pRL-Trim59-3’-UTR. Moreover, miR-4698 mimic inhibited the expression of Trim59. Overexpression of Trim59 abrogated the inhibitory effects of miR-4698. In conclusion, these data show that miR-4698-Trim59 axis plays a tumor suppressive role in HCC.

Background and objective TRIM proteins are important members of E3 ubiquitin ligases, and many studies have confirmed that TRIM family members play an important role in the development of various tumors. We found that TRIM59 expression level in non-small cell lung cancer (NSCLC) was significantly increased through second-generation sequencing. The purpose of this study was to investigate the expression of TRIM59 in NSCLC and its relationship with the clinicopathological parameters as well as the prognosis of patients. Methods The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were excavated to analyze the expression of TRIM59 mRNA in NSCLC and its relationship with the prognosis of patients; The expression of TRIM59 protein in 90 tumor tissues and adjacent tissues was detected by immunohistochemical staining, and the relationship between the expression of TRIM59 protein and clinicopathological parameters and prognosis was analyzed. Results Overexpression of TRIM59 mRNA in tumor tissues predicted poor prognosis. The expression level of TRIM59 protein was significantly higher in tumor tissues than in adjacent tissues, and TRIM59 protein expression was correlated with tumor size (P=0.007), tumor differentiation (P=0.009), tumor-node-metastasis (TNM) stage (P=0.003) and lymph node metastasis (P=0.003). Multivariate Cox regression analyses showed that along with TNM stage, overexpression of TRIM59 could be considered an independent prognostic factor for NSCLC patients. Conclusion The expression of TRIM59 is closely related to the prognosis of NSCLC patients, and it is an independent risk factor for NSCLC patients.

Neuroblastoma, predominantly afflicting young individuals, is characterized as an embryonal tumor, with poor prognosis primarily attributed to chemoresistance. This study delved into the impact of tripartite motif (TRIM) 59, an E3 ligase, on neuroblastoma development and chemosensitivity through mediating ferroptosis and the involvement of the tumor suppressor p53. Clinical samples were assessed for TRIM59 and p53 levels to explore their correlation with neuroblastoma differentiation. In neuroblastoma cells, modulation of TRIM59 expression, either through overexpression or knockdown, was coupled with doxorubicin hydrochloride (DOX) or ferrostatin-1 (Fer-1) therapy. In vivo assessments examined the influence of TRIM59 knockdown on neuroblastoma chemosensitivity to DOX. Co-immunoprecipitation and ubiquitination assays investigated the association between TRIM59 and p53. Proliferation was gauged with Cell Counting Kit-8, lipid reactive oxygen species (ROS) were assessed via flow cytometry, and protein levels were determined by Western blotting. TRIM59 expression was inversely correlated with neuroblastoma differentiation and positively linked to cell proliferation in response to DOX. Moreover, TRIM59 impeded lipid ROS generation and ferroptosis by directly interacting with p53, promoting its ubiquitination and degradation in DOX-exposed neuroblastoma cells. Fer-1 countered the impact of TRIM59 knockdown on neuroblastoma, while TRIM59 knockdown enhanced the therapeutic efficacy of DOX in xenograph mice. This study underscores TRIM59 as an oncogene in neuroblastoma, fostering growth and chemoresistance by suppressing ferroptosis through p53 ubiquitination and degradation. TRIM59 emerges as a potential strategy for neuroblastoma therapy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Objective: To investigate the effect of tripipartite motif 59 (TRIM59) expression interference on the chemosensitivity of daunorubicin (DNR) in chronic myeloid leukemia (CML) K562 cells and the related molecular mechanism., Methods: The expressions of TRIM59 mRNA in bone marrow tissues of patients with CML and K562 cells were detected by RT-qPCR. Liposome-based transfection technology was used to transfect TRIM59-specific siRNA (si-TRIM59) into K562 cells which then were treated with DNR. The proliferation and apoptosis of cells were detected by CCK-8 assay and flow cytometry, respectively, and the expressions of apoptosis-related protein and Wnt/β-catenin signaling pathway-related protein were detected by Western blot., Results: Compared with the bone marrow tissue of CML patients at the time of initial treatment, the expression of TRIM59 mRNA in bone marrow tissue of CML patients at the time of chemotherapy resistance was significantly increased ( P <0.05). Compared with control group, the cell proliferation inhibition rate and apoptosis rate in si- TRIM59 group and DNR group were significantly increased ( P <0.05), the expression of Bax, Caspase3 and Cleaved-Caspase3 protein were significantly increased ( P <0.05), while the expressions of Bcl-2, Wnt3α, GSK-3β protein and the ratio of p-β-catenin/β-catenin were significantly decreased ( P <0.05). Compared with si- TRIM59 group and DNR group, the proliferation inhibition rate and apoptosis rate of si- TRIM59 +DNR group were significantly increased ( P <0.05), the expression of Bax, Caspase3 and Cleaved-Caspase3 protein were significantly increased, while the expression of Bcl-2, Wnt3α, GSK-3β protein and the ratio of p-β-catenin/β-catenin were significantly decreased ( P <0.05)., Conclusion: TRIM59 expression interference may enhance the chemosensitivity of K562 cells to DNR, and its mechanism may be related to the regulation of Wnt/β-catenin signaling pathway.

Importance: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has tragically claimed millions of lives through coronavirus disease 2019 (COVID-19), and there remains a critical gap in our understanding of the precise molecular mechanisms responsible for the associated fatality. One key viral factor of interest is the SARS-CoV-2 ORF3a protein, which has been identified as a potent inducer of host cellular proinflammatory responses capable of triggering the catastrophic cytokine storm, a primary contributor to COVID-19-related deaths. Moreover, ORF3a, much like the spike protein, exhibits a propensity for frequent mutations, with certain variants linked to the severity of COVID-19. Our previous research unveiled two distinct types of ORF3a mutant proteins, categorized by their subcellular localizations, setting the stage for a comparative investigation into the functional and mechanistic disparities between these two types of ORF3a variants. Given the clinical significance and functional implications of the natural ORF3a mutations, the findings of this study promise to provide invaluable insights into the potential roles undertaken by these mutant ORF3a proteins in the pathogenesis of COVID-19., Competing Interests: The authors declare no conflict of interest.

TRIM59 is a member of the tripartite motif containing (TRIM) protein family. It functions as an E3 ubiquitin ligase through its RING domain and is expressed by multiple types of cells. Physiogically, TRIM59 is involved in development, immune response, and the invasion and metastasis of tumors. In this review, we first describe the structure, expression, and subcellular location of TRIM59. Then, we summarize emerging evidence for TRIM59 in immunological diseases including infection, vascular diseases, autoimmunity, and tumor immunity. Additionally, we discuss important molecular signaling pathways that mediate TRIM59 activity. Altogether, the accumulating evidence suggests that manipulating TRIM59 levels and activity may open an avenue for innovative therapies for immune diseases and tumors.

Tripartite motif containing 59 (TRIM59) functions as an oncoprotein in various human cancers including ovarian cancer. In this study, we found that TRIM59 gene amplification was prevalent in ovarian cancer tissues, and its amplification was significantly correlated with poorer overall survival. Moreover, knockdown of TRIM59 in SKOV3 and OVCAR3 cells, which had relatively high level of TRIM59, suppressed glucose uptake and lactate production. TRIM59 knockdown also decreased the expression of c‐Myc and lactate dehydrogenase A, and the phosphorylation of extracellular signal‐regulated kinase (ERK). TRIM59 overexpression in A2780 cells, which expressed low level of TRIM59, showed reverse effects. Notably, treatment with an ERK inhibitor (PD98059) completely abolished the oncogenic effects of TRIM59 overexpression. Interestingly, TRIM59 increased the ubiquitination of MAP kinase phosphatase 3 (MKP3), which may dephosphorylate and inactivate ERK. Ectopic expression of MKP3 inhibited the promoting effects of TRIM59 on glycolysis and the phosphorylation of ERK. TRIM59 protein expression was negatively correlated with MKP3 protein expression in ovarian cancer tissues. Finally, TRIM59 amplification potently affected the anticancer effect of 3‐bromopyruvate, an inhibitor of glycolysis, in ovarian cancer cells and patient‐derived xenograft. In conclusion, these results suggest that TRIM59 may regulate glycolysis in ovarian cancer via the MKP3/ERK pathway. [ABSTRACT FROM AUTHOR]

Sepsis is associated with bacterial invasion and inflammation and has a high mortality rate. Previous studies have demonstrated that tripartite motif 59 (TRIM59) was involved in NF-κB signaling and could promote phagocytosis of macrophages, but the role of TRIM59 in sepsis is still unknown. In our study, we found that TRIM59 was downregulated in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs). In the cecal ligation and puncture (CLP) sepsis mice model, the mortality of Trim59flox/floxLyz-Cre (Trim59-cKO) mice was higher, the immune cell infiltration and damage of liver and lung were more severe, and bacteria burden was increased. We also found that TRIM59 altered the production of pro-inflammation cytokines, as well as macrophage phagocytosis ability. Further analysis indicated that NF-κB signal pathway and Fcγ receptors might be involved in these regulations. Our study demonstrated for the first time that TRIM59 protects mice from sepsis by regulating inflammation and phagocytosis in macrophages.

Exosomes derived from human umbilical cord mesenchymal stem cells (HUCMSCs) expressing microRNAs (miRs) have been highlighted as important carriers for gene or drug therapy. Hence, this study aimed to explore the role of exosomal miR-148b-3p from HUCMSCs in breast cancer. Clinical samples subjected to RT-qPCR detection revealed that miR-148b-3p was poorly expressed, while tripartite motif 59 (TRIM59) was highly expressed in breast cancer tissues. Online analyses available at miRanda, TargetScan, and miRbase databases revealed that miR-148b-3p could bind to TRIM59, while dual-luciferase reporter gene assay further verified that TRIM59 was a target gene of miR-148b-3p. Next, miR-148b-3p mimic or inhibitor and siRNA against TRIM59 were delivered into the breast cancer cells (MDA-MB-231) to alter the expression of miR-148b-3p and TRIM59 so as to evaluate their respective effects on breast cancer cellular processes. Evidence was obtained demonstrating that miR-148b-3p inhibited cell proliferation, invasion, and migration, but promoted cell apoptosis in breast cancer by down-regulating TRIM59. Next, MDA-MB-231 cells were co-cultured with the exosomes derived from HUCMSCs expressing miR-148b-3p. The results of co-culture experiments demonstrated that HUCMSCs-derived exosomes carrying miR-148b-3p exerted inhibitory effects on MDA-MB-231 progression in vitro. In vivo experimentation further confirmed the anti-tumor effects of HUCMSCs-derived exosomes carrying miR-148b-3p. Taken together, HUCMSC-derived exosomes carrying miR-148b-3p might suppress breast cancer progression, which highlights the potential of exosomes containing miR-148b-3p as a promising therapeutic approach for breast cancer treatment.

The tripartite motif (TRIM) protein family are implicated in a wide array of cellular processes, including cell growth, differentiation, apoptosis and inflammation. This study aimed to investigate the specific function of TRIM59 in chondrocytes and its association with the pathophysiology of osteoarthritis (OA). We observed the downregulated TRIM59 expression in OA cartilage compared to normal tissues. Overexpression of TRIM59 suppressed interleukin 1 beta (IL-1β)-induced extracellular matrix (ECM) metabolic imbalance, proinflammatory cytokine production, apoptosis and decrease in cell viability. Mechanistic analyses further revealed that IL-1β-induced activation of the NF-κB and JAK2/STAT3 pathway is suppressed upon TRIM59 overexpression. TRIM59 expression was consistently decreased in a rat OA model in vivo , and its overexpression led to inhibition of matrix metallopeptidase-13 (MMP-13) production, proinflammatory cytokine levels and increased collagen type II (collagen II) and aggrecan synthesis. Our data collectively suggest that TRIM59 plays a critical in OA development through regulation of NF-κB and JAK2/STAT3 signaling pathway. Pharmacological upregulation of TRIM59 may therefore present an effective novel therapeutic approach for OA. • TRIM59 expression is downregulated in human OA cartilage and IL-1β-induced chondrocytes. • TRIM59 attenuates IL-1β-induced chondrocyte apoptosis, inflammatory response and matrix degradation. • TRIM59 counteracted cartilage matrix degradation in the rat OA model. • TRIM59 represses IL-1β activated NF-κB and JAK2/STAT3 signaling pathway activation in chondrocytes. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Myocardial ischemia reperfusion injury (MIRI) is a common factor in heart-related diseases. The aim of this study was to explore the effect of TRIM59 gene on MIRI and its mechanism. MATERIALS AND METHODS: Rats were used to construct MIRI models, and TRIM59 gene was overexpressed in myocardium by Entranster technique to detect the effects of TRIM59 on myocardial oxidative stress, myocardial injury, and ATPase. In addition, rat myocardial H9c2 cells were cultured, and a hypoxia-reoxygenation model of H9c2 cells was constructed to detect the effect of TRIM59 overexpression on the inflammation and apoptosis of H9c2 cells. Finally, the PI3K/Akt signaling pathway inhibitor LY294002 was used to study the effect of TRIM59 on the PI3K/Akt signaling pathway. RESULTS: Overexpression of TRIM59 in vivo effectively reduced the expressions of MDA, CK, and LDH, and increased the expression of SOD and the activity of Na+-K+-ATPase and Ca2+-Mg2+-ATPase. In addition, overexpression of TRIM59 in H9c2 cells significantly reduced the expression of inflammatory cytokines (IL-1β, IL-6, and TNF-α) and oxidative stress (ROS) levels. TRIM59 also significantly increased the activity of PI3K/Akt signaling pathway and promoted the phosphorylation of Akt. CONCLUSIONS: TRIM59 reduces the level of inflammation and apoptosis of myocardial cells caused by MIRI by activating the PI3K/Akt signaling pathway, thereby reducing myocardial injury. [ABSTRACT FROM AUTHOR]

Tripartite motif 59 (TRIM59) is a member of Tripartite motif protein family, which is frequently increased in many human cancers. However, the molecular mechanism of TRIM59 in hepatocellular carcinoma (HCC) has not been fully elucidated. In this study, we report that TRIM59 plays an essential role in growth of HCC. We analyzed RNA sequencing data to explore abnormally expressed TRIM59 in HCC. The effects of TRIM59 on HCC were investigated through in vitro and in vivo assays (i.e., CCK-8 assay, colony formation assay, flow cytometry assay, xenograft model, immunohistochemistry, immunofluorescence and western blot). The mechanism of TRIM59 action was explored through co-immunoprecipitation, immunofluorescence, mass spectrometry and bioinformatics. TRIM59 expression is up-regulated in HCC tissues. A high level of TRIM59 expression is correlated with poor overall and disease-free survival of HCC patients. Knockdown of TRIM59 attenuated proliferation, induced cells arrested at G1/S phase and reduced tumor growth in the mouse xenograft model. Ectopic expression of TRIM59 had the opposite results. Mechanistically, TRIM59 promoted growth and regulated cell cycle. Further studies indicated that TRIM59 might interacted physically with PPM1B, which has been reported to negatively regulate CDKs phosphorylation. We also discovered that TRIM59 increased degradation of PPM1B. TRIM59 overexpression in HCC patients correlated with reduced expression of PPM1B and increased CDKs phosphorylation and cell cycle proteins. Our findings demonstrate that TRIM59 promotes growth by PPM1B/CDKs signaling pathway, indicating a new prognostic biomarker candidate and a potential antitumor target for HCC. [ABSTRACT FROM AUTHOR]

Sepsis is associated with bacterial invasion and inflammation and has a high mortality rate. Previous studies have demonstrated that tripartite motif 59 (TRIM59) was involved in NF-κB signaling and could promote phagocytosis of macrophages, but the role of TRIM59 in sepsis is still unknown. In our study, we found that TRIM59 was downregulated in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs). In the cecal ligation and puncture (CLP) sepsis mice model, the mortality of Trim59 flox / flox Lyz-Cre (Trim59 -cKO) mice was higher, the immune cell infiltration and damage of liver and lung were more severe, and bacteria burden was increased. We also found that TRIM59 altered the production of pro-inflammation cytokines, as well as macrophage phagocytosis ability. Further analysis indicated that NF-κB signal pathway and Fcγ receptors might be involved in these regulations. Our study demonstrated for the first time that TRIM59 protects mice from sepsis by regulating inflammation and phagocytosis in macrophages. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Lung Cancer is the property of Chinese Journal of Lung Cancer and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Exosomes derived from human umbilical cord mesenchymal stem cells (HUCMSCs) expressing microRNAs (miRs) have been highlighted as important carriers for gene or drug therapy. Hence, this study aimed to explore the role of exosomal miR-148b-3p from HUCMSCs in breast cancer. Clinical samples subjected to RT-qPCR detection revealed that miR-148b-3p was poorly expressed, while tripartite motif 59 (TRIM59) was highly expressed in breast cancer tissues. Online analyses available at miRanda, TargetScan, and miRbase databases revealed that miR-148b-3p could bind to TRIM59, while dual-luciferase reporter gene assay further verified that TRIM59 was a target gene of miR-148b-3p. Next, miR-148b-3p mimic or inhibitor and siRNA against TRIM59 were delivered into the breast cancer cells (MDA-MB-231) to alter the expression of miR-148b-3p and TRIM59 so as to evaluate their respective effects on breast cancer cellular processes. Evidence was obtained demonstrating that miR-148b-3p inhibited cell proliferation, invasion, and migration, but promoted cell apoptosis in breast cancer by down-regulating TRIM59. Next, MDA-MB-231 cells were co-cultured with the exosomes derived from HUCMSCs expressing miR-148b-3p. The results of co-culture experiments demonstrated that HUCMSCs-derived exosomes carrying miR-148b-3p exerted inhibitory effects on MDA-MB-231 progression in vitro. In vivo experimentation further confirmed the anti-tumor effects of HUCMSCs-derived exosomes carrying miR-148b-3p. Taken together, HUCMSC-derived exosomes carrying miR-148b-3p might suppress breast cancer progression, which highlights the potential of exosomes containing miR-148b-3p as a promising therapeutic approach for breast cancer treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • Reduced TRIM59 levels in vivo and in vitro negatively correlate with disease progression in patients with IBD and colitis model mice. • Intestinal epithelial cells-specific Trim59 knockout (IEC-KO Trim59) promotes DSS-triggered colitis phenotypes in vivo. • Intestinal epithelial cells-specific Trim59 overexpression (IEC-OE Trim59) mitigates DSS-triggered colitis phenotypes in vivo. • TRIM59 alleviates colitis progression by regulating NRF2/KEAP1 signaling. • TRIM59 protects against colitis by directly interacting with KEAP1, thereby facilitating its ubiquitination degradation. Elevated evidence has reported the important role of oxidative stress injury and inflammatory response in the progression of colitis. Tumor Suppressor TSBF1, TRIM59, is a ubiquitin E3 ligase and mediates immune response. However, the underlying molecular function of TRIM59 on regulation of colitis is still not understood. In the current study, we identify the TRIM59 as a critical and novel endogenous suppressor of kelch-like ECH-associated protein 1 (KEAP1), and we also determine that TRIM59 is a KEAP1-interacting partner protein that catalyses its ubiquitination and degradation in intestinal epithelial cells (IEC). Moreover, IEC-specific loss of the Trim59 disrupts colon metabolic homeostasis, accompanied by intestinal oxidative stress injury, elevated endogenous reactive oxygen species (ROS) production and pro-inflammatory cytokines release, significantly promotes acute or chronic colitis progression. Conversely, transgenic mice with Trim59 overexpression by adeno-associated virus (AAV)-induced Trim59 gene therapeutics mitigates colitis in acute or chronic colitis rodent models and in vitro experiments. Mechanistically, in response to onset of colitis, TRIM59 directly interacts with KEAP1 and promotes ubiquitin–proteasome degradation, thus results in NRF2 activation and its downstream cascade anti-oxidative stress-related pathway activation, which facilitates anti-oxidant defense and reduces tissue damage. All the findings elucidated the potential role of TRIM59 in colitis progression by mediating KEAP1 deactivation and degradation, and could be considered as a therapeutic target for the treatment of such disease. [ABSTRACT FROM AUTHOR]

Wei Chen,1,* Kai Zhao,2,* Chenkui Miao,2,* Aiming Xu,2 Jianzhong Zhang,2 Jundong Zhu,2 Shifeng Su,2 Zengjun Wang2 1Department of Urology, Nanjing First Hospital, Nanjing Medical University, 2State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: The evolutionarily conserved genes that encode the tripartite motif (TRIM) protein family are involved in various biological processes, including cellular immunity, inflammatory reaction, antiviral activity, and tumor progression. One member of this protein family, Trim59, has been reported as a novel biomarker for the occurrence and progression of multiple human carcinomas, such as lung cancer, gastric cancer, cervical cancer, and osteosarcoma. However, little is known about the relationship between Trim59 and bladder carcinogenesis. In this study, we examined the expression of Trim59 in bladder cancer (Bca) specimens and cell lines, and investigated its biological roles in Bca cell lines. We found that Trim59 was upregulated in Bca tissues and cell lines. In addition, using transwell chamber assays and the cell scratch test, we determined that knockdown of Trim59 significantly inhibited the epithelial-mesenchymal transition (EMT) and the processes of cell invasion and migration in Bca cell lines. Furthermore, we found that downregulated Trim59 expression could also inhibit cell proliferation and promote apoptosis. As a result, we demonstrated that the effects of Trim59-induced EMT and invasion/migration in Bca cells were achieved by the activation of the transforming growth factor beta/Smad2/3 signaling pathway. Our findings also revealed that Trim59 can present oncogenic activity, and may serve as a novel candidate target for bladder carcinoma treatment. Keywords: Trim59, bladder carcinoma, EMT, metastasis, TGF-β, Smad2/3

Abstract Aim We analysed multiple microarray datasets in the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) DataSets for messenger RNAs (mRNAs) whose expression is apparently increased in human cholangiocarcinoma (CCA) samples, compared with that in the adjacent normal biliary epithelial tissue. The results revealed that the expression of tripartite motif-containing 59 (TRIM59) was significantly increased in the CCA tissue samples. TRIM59 is a member of the tripartite motif (TRIM) protein family, which contains a highly conserved N-terminal—an interesting new gene (RING) domain regulating transcriptional factors and tumorigenesis. In the present study, we investigated the effects of TRIM59 expression on tumour growth in CCA. Materials and methods After analyzing the microarray datasets from the TCGA database and GEO DataSets, we screened out 291 target genes, which are significantly overexpressed in CCA tissues, and TRIM59 was one of them. The quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemistry were performed to determine the expression of TRIM59 in CCA tissues (n = 65) and cell lines. Kaplan–Meier survival analysis was conducted to assess the prognosis of TRIM59 in patients with CCA. A specific siRNA (siRNA-1008) was used to inhibit the expression of TRIM59 in HCCC9810 and HUCCT1 cell lines. The effects of TRIM59 silencing on cell proliferation were assessed by the CCK-8, colony-formation, and EDU incorporation assays. Furthermore, the effects of TRIM59 knockdown on cell apoptosis and cell cycle were determined by flow cytometry. The in vivo effects were evaluated using a mouse tumorigenic model. Western blotting was also performed to verify the relationship between knockdown of TRIM59 and activation of the PI3K/AKT/mTOR pathway. Results TRIM59 was highly expressed in CCA tissues. The knockdown of TRIM59 obviously reduced the proliferation and colony formation abilities of CCA cells in vitro and in vivo. Furthermore, the cell apoptosis analysis results showed that TRIM59 silencing apparently promoted CCA cell apoptosis by the mitochondrial pathway. Our preliminary results indicate that the down-regulation of TRIM59 levels might restrict the PI3K/AKT/mTOR signalling pathway. Conclusions Our study revealed that TRIM59 is up-regulated in CCA tissues and cell lines and promoted CCA cell proliferation, possibly by affecting the PI3K/AKT/mTOR signalling pathway. Highlights • TRIM59 is clinically overexpressed in cholangiocarcinoma. • Knockdown of TRIM59 reduced the proliferation and colony formation abilities of cholangiocarcinoma cells in vitro and in vivo. • TRIM59 silencing promoted cholangiocarcinoma cell apoptosis via the mitochondrial pathway. • Knockdown of TRIM59 inhibited the activation of PI3K/AKT/mTOR pathway in cholangiocarcinoma cells. [ABSTRACT FROM AUTHOR]

The relationship between TRIM59 and drug resistance is elusive despite of its multiple uncovered roles in human cancers. Here we aimed to characterize the expression status of TRIM59 in gefitinib-resistant EGFR mutant lung adenocarcinoma cells and elucidate its mechanism underlying the drug resistance. Gefitinib-resistant cell lines were established by progressive dosage. Relative expression of TRIM59 was determined by both real-time PCR and Western blot. Target gene knockdown was achieved by specific shRNAs. Cell viability was measured by MTT assay. Cell apoptosis was analyzed by flow cytometry with Annexin V/7-AAD double staining. Cell proliferation was determined by clonogenic formation assay. Migration and invasion capacities were detected using transwell chamber assay. Direct interaction between TRIM59 and STAT3 was analyzed by co-immunoprecipitation assay. We first observed overexpression of TRIM59 in gefitinib-resistant EGFR mutant lung adenocarcinoma cells. ShRNA-mediated knockdown of TRIM59 significantly inhibited cell viability and stimulated apoptosis. Meanwhile, TRIM59-deficiency suppressed cell migration and invasion. We further identified the interaction between TRIM59 and STAT3. TRIM59-deficiency remarkably impaired the activation of STAT3 signaling. STAT3-specific shRNAs significantly re-sensitized TRIM59-proficient EGFR mutant lung adenocarcinoma cells to gefitinib. Our data characterized aberrant TRIM59 overexpression in gefitinib-resistance EGFR mutant lung adenocarcinoma cells, and indicated the potential involvement of TRIM59-STAT3 signaling in the occurrence of gefitinib-resistance. Unlabelled Image [ABSTRACT FROM AUTHOR]

In view of the recognized anti-tumor properties of eugenol against non-small cell lung cancer (NSCLC) in cell culture, here we further set out to investigate the potential therapeutic effect of eugenol in vivo and elucidate the underlying molecular mechanism. The relative expression levels of TRIM59 and p65 in NSCLC were quantified by real-time polymerase chain reaction. Xenograft tumor model was established with TRIM59-deficient H1975 cells, and tumor progression was monitored. Kaplan-Meier's analysis was performed to measure overall survival. Protein levels of TRIM59 and p65 in xenograft tumor were determined by western blot. Direct binding of p65 on the TRIM59 promoter was analyzed by chromatin immunoprecipitation assay, and the regulatory effect was interrogated with luciferase reporter assay. Both TRIM59 and p65 were up-regulated in NSCLC. Eugenol treatment significantly inhibited xenograft tumor progression and prolonged the overall survival of tumor-bearing mice. Mechanistically, eugenol suppressed p65 expression, which subsequently decreased TRIM59 expression. TRIM59 deficiency fully recapitulated the anti-tumoral phenotype elicited by eugenol. Ectopic expression of TRIM59 completely abolished the tumor suppressive effect of eugenol, which underlined the predominant role of TRIM59 in mediating the signaling downstream of eugenol treatment. Eugenol inhibited NSCLC via repression NF-κB-TRIM59 pathway. [ABSTRACT FROM AUTHOR]

Notch exerts important functions in cell proliferation, survival, and differentiation, which plays a critical role in tumor development when aberrantly activated. Mastermind‐like protein 1 (MAML1) has been functioning as crucial coactivators of Notch receptors and is required for stable formation of Notch transcriptional complexes. However, the mechanism whereby MAML1 induces T‐cell acute lymphoblastic leukemia (T‐ALL) tumorigenesis is largely unknown. The CCK‐8 and flow cytometry assay were performed to examine the effect of MAML1 knockdown on T‐ALL cell proliferation, apoptosis, and cell cycle. The expression of MAML1, cell cycle, and apoptosis‐related gene, as well as TRIM family members and specific protein 1 (SP1) was measured by western blot analysis and qPCR. Our results showed that MAML1 knockdown significantly inhibited cell proliferation and induced G0/G1 cell cycle arrest and apoptosis in Jurkat and MOLT‐4 cells. Cell cycle and apoptosis‐related gene expression, including CDK2, Bcl‐2, Bax, and Bad, was modified by the MAML1 knockdown. MAML1 knockdown obviously inhibited the CDK2 and Bcl‐2 expression and increased the Bax, p53, and Bad expression. Moreover, the TRIM family members, including TRIM13, TRIM32, TRIM44, and TRIM59, were significantly decreased by the MAML1 knockdown, with the highest decrease detected in TRIM59 expression. Interesting, overexpression of SP1 not only increased the expression of MAML1 and TRIM59, but also promoted the promoter activation of TRIM59. Taken together, knockdown of MAML1 inhibits proliferation and induces apoptosis of T‐ALL cells through SP1‐dependent inactivation of TRIM59, and therefore suggest that MAML1‐SP1‐TRIM59 axis may serve as potentially interesting therapeutic targets for treatment of T‐ALL. Knockdown of mastermind‐like protein 1 (MAML1) inhibited cell proliferation, arrested cell cycle, and induced apoptosis of T‐cell acute lymphoblastic leukemia (T‐ALL) cells through specific protein 1 (SP1)‐dependent inactivation of TRIM59, and coexpression of MAML1 may reduce the intracellular domain of NOTCH1‐induced activation of the target promoters.Therefore, these suggested that MAML1–SP1–TRIM59 axis may induces T‐ALL tumorigenesis by the Notch signaling pathway. [ABSTRACT FROM AUTHOR]

Lung cancer (LC) is a devastating malignancy with no effective treatments, due to its complex genomic profile. Using bioinformatics analysis and immunohistochemical of lung carcinoma tissues, we show that TRIM59 as a critical oncoprotein relating to LC proliferation and metastasis. In this study, high TRIM59 expression was significantly correlated with lymph node metastasis, distant metastasis, and tumour stage. Furthermore, up‐regulation of TRIM59 expression correlated with poorer outcomes in LC patients. Mechanistically, TRIM59 play a key role in promoting LC growth and metastasis through regulation of extracellular‐signal regulated protein kinase (ERK) signalling pathway and epithelial‐to‐mesenchymal transition (EMT)‐markers, as validated by loss‐of‐function studies. In‐depth bioinformatics analysis showed that there is preliminary evidence of co‐expression of TRIM59 and cyclin dependent kinase 6 (CDK6) in LC. Notably, CDK6 expression significantly decreased when TRIM59 was knocked down in the LC cells. In contrast, exogenous up‐regulation of TRIM59 expression also induced significant increases in the expression of CDK6. Moreover, the expression of CDK6 was also inhibited by the ERK signalling inhibitor, U0126. The results of both loss‐ and gain‐of‐function studies showed that TRIM59 could regulate the expression of CDK6. Collectively, these data provide evidence that TRIM59 is involved in lung carcinoma growth and progression possibly through the induction of CDK6 expression and EMT process by activation of ERK pathway. [ABSTRACT FROM AUTHOR]

Macroautophagy/autophagy is a multistep cellular process that sequesters cytoplasmic components for lysosomal degradation. BECN1/Beclin1 is a central protein that assembles cofactors for the formation of a BECN1-PIK3C3-PIK3R4 complex to trigger the autophagy protein cascade. Discovering the regulators of BECN1 is important for understanding the mechanism of autophagy induction. Here, we demonstrate that TRIM59, a tripartite motif protein, plays an important role in autophagy regulation in non-small cell lung cancer (NSCLC). On the one hand, TRIM59 regulates the transcription of BECN1 through negatively modulating the NFKB pathway. On the other hand, TRIM59 regulates TRAF6 induced K63-linked ubiquitination of BECN1, thus affecting the formation of the BECN1-PIK3C3 complex. We further demonstrate that TRIM59 can mediate K48-linked ubiquitination of TRAF6 and promote the proteasomal degradation of TRAF6. Taken together, our findings reveal novel dual roles for TRIM59 in autophagy regulation by affecting both the transcription and the ubiquitination of BECN1. Abbreviations: ACTB: actin beta; BECN1: beclin 1; CHX: cycloheximide; CQ: chloroquine; GFP: green fluorescent protein; HA: haemagglutinin tag; His: polyhistidine tag; LC3B: microtubule associated protein 1 light chain 3 beta; NFKB: nuclear factor kappa B; NFKBIA: NFKB inhibitor alpha; NSCLC: non-small cell lung cancer; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; RELA: RELA proto-oncogene, NF-kB subunit; SQSTM1: sequestosome 1; tGFP: Turbo green fluorescent protein; TRAF6: TNF receptor associated factor 6; TRIM59: tripartite motif containing 59; B: ubiquitin [ABSTRACT FROM AUTHOR]

Age prediction helps investigation to narrowing down the number of potential suspects and give more reliable predicted appearance. However, since it is not known if some of the widely used methylation markers (ELOVL2, C1orf132, TRIM59, KLF14 and FHL2) are applicable as age predictors in the Italian population, in this study we collected and analyzed a set of saliva samples from 96 Italian individuals aged 19–67 years. All DNA samples were quantified, bisulfite-converted, amplified with monoplex and analyzed using PyroMark Q48 Autoprep (Qiagen). The age prediction was performed according to reference (Zbieć-Piekarska et al. [1]). Preliminary results shown a linear correlation between the methylation markers studied and age in the Italian samples, with a Pearson correlation coefficient (PCC) of 0.75 and the value of median absolute deviation (MAD) of 5.4. The MAD value observed with group 1 (age 20 s or less) was 2.8, with group 2 (30 s) was 4.5, with group 3 (40 s) was 4.7 and with group 4 (50 s or more) was 5.4. If we take the assumption that age prediction is correct when predicted age is in the range of max ±5 years of the actual age, the number of correct prediction decrease with increasing of the age group. Moreover, in contrast of what expected, our data set has shown a bias in the underestimating of predicted age at the increasing of chronological age (20% group 1, 60% group 2, 79% group 3 and 88% group 4). This experiment suggest to increase the number of different population sampled since DNA methylation could be affected by genetic variation, environmental and lifestyle variation. [ABSTRACT FROM AUTHOR]

Objective · To demonstrate the effect of TRIM59 on gliomagenesis and the molecular mechanism. Methods · TRIM59 protein expression in glioma specimens was analyzed by immunohistochemical staining, and in several glioma cell lines by Western blotting and quantative PCR. After TRIM59 was knocked down by shRNAs, cell proliferation, migration, colony formation, and orthotopic xenograft brain tumor development were detected. The signaling pathway of TRIM59 in gliomas was also explored by RNA-Seq and KEGG PATHWAY analyses. Results · The levels of TRIM59 protein expression in clinical glioma specimens were positively correlated with glioma malignancy. TRIM59 was highly expressed in LN229 and U87 glioma cells compared with normal human astrocytes. Knockdown of TRIM59 in these two cell lines with lentivirus-mediated shRNAs inhibited their proliferation, migration, and colony formation. Compared with the control xenograft models, knockdown of TRIM59 significantly inhibited glioma tumor growth. RNASeq and KEGG PATHWAY analyses identified that TRIM59 knockdown down-regulated 306 genes, among which PI3K/AKT signal pathway-related genes were the most. Moreover, TRIM59 knockdown suppressed AKT phosphorylation, whereas overexpression of a constitutively actived AKT (Myr-AKT) rescued TRIM59 knockdown-inhibited cell proliferation. Conclusion · TRIM59 is a new glioma oncogene, which may take effect through activating PI3K/AKT signaling pathway. [ABSTRACT FROM AUTHOR]

The tripartite motif (TRIM) family of proteins is a class of highly conservative proteins that have been implicated in multiple processes. TRIM59, one member of the TRIM family, has now received recognition as a key regulator in the development and progression of human diseases. However, its role in human tumorigenesis has remained largely unknown. In this study, the effects of TRIM59 expression on cell proliferation and migration were investigated in human cervical cancer cells. The expression of TRIM59 in clinical cervical cancer tissues and cervical cancer cells was initially determined by RT-PCR and Western blot. Specific shRNA against TRIM59 was then employed to knock down the expression of TRIM59 in cervical cancer lines HeLa and SiHa. The effects of TRIM59 knockdown on cell proliferation was assessed by MTT assay and colony formation assay. Transwell assay was conducted to reveal cell migration and invasion abilities before and after TRIM59 knockdown. Our results showed that the expression of TRIM59 was significantly elevated in cervical cancers. Knockdown of TRIM59 significantly inhibited cell proliferation and colony formation as well as cell migration and invasion abilities in cervical cancer HeLa and SiHa cells. Cell cycle progression analysis showed that TRIM59-depleted cells preferred to accumulate in the S phase. These data suggest that TRIM59 is a potential target that promotes the progression of cervical cancer. [ABSTRACT FROM AUTHOR]

The evolutionarily conserved genes that encode the tripartite motif (TRIM) protein family are involved in various biological processes, including cellular immunity, inflammatory reaction, antiviral activity, and tumor progression. One member of this protein family, Trim59, has been reported as a novel biomarker for the occurrence and progression of multiple human carcinomas, such as lung cancer, gastric cancer, cervical cancer, and osteosarcoma. However, little is known about the relationship between Trim59 and bladder carcinogenesis. In this study, we examined the expression of Trim59 in bladder cancer (Bca) specimens and cell lines, and investigated its biological roles in Bca cell lines. We found that Trim59 was upregulated in Bca tissues and cell lines. In addition, using transwell chamber assays and the cell scratch test, we determined that knockdown of Trim59 significantly inhibited the epithelial-mesenchymal transition (EMT) and the processes of cell invasion and migration in Bca cell lines. Furthermore, we found that downregulated Trim59 expression could also inhibit cell proliferation and promote apoptosis. As a result, we demonstrated that the effects of Trim59-induced EMT and invasion/migration in Bca cells were achieved by the activation of the transforming growth factor beta/Smad2/3 signaling pathway. Our findings also revealed that Trim59 can present oncogenic activity, and may serve as a novel candidate target for bladder carcinoma treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Members of the tripartite motif (TRIM) protein family contain a highly conserved N-terminal really interesting new gene (RING) domain that is involved in regulating transcriptional factors and tumor suppressors. In this study, the effects of TRIM59 expression on tumor growth were investigated in prostate cancer. MATERIALS AND METHODS: The expression of TRIM59 in prostate cancer tissues (n = 15) and prostate cancer cell lines was determined by quantitative reverse transcriptase-PCR (qRT-PCR), Western blotting, and immunohistochemistry. A specific shRNA targeting TRIM59 was employed to knockdown TRIM59 expression in the prostate cancer cell lines PC3 and DU145. The effects of TRIM59 knockdown on cell proliferation were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays. The effects on cell cycle progression were determined by flow cytometry, and a xenograft mouse model of prostate cancer was generated to determine the in vivo effects of TRIM59 knockdown. The effects on cell cycle regulators were determined by Western blotting. RESULTS: TRIM59 was highly expressed in prostate cancer tissues. Knockdown of TRIM59 significantly inhibited cell proliferation and colony formation, and cell cycle analysis showed that TRIM59-depleted cells accumulated in S-phase. TRIM59 knockdown was shown to inhibit tumorigenesis in mice. In addition, the cell cycle regulators CDC25A, CDC2, and cyclin B1 were decreased by TRIM59 shRNAmediated knockdown. CONCLUSIONS: Our study suggests that TRIM59 promotes prostate cancer cell proliferation, possibly through its effects on cell cycle progression. [ABSTRACT FROM AUTHOR]

Receptor-driven selective macroautophagy/autophagy delivers ubiquitinated targets for autophagosomal clearance to maintain metabolic homeostasis and orchestrate reparative inflammatory responses. Deregulated autophagy is linked to tumor progression, but the exact mechanisms of selective autophagy in the spatiotemporal control of cell polarity signaling components during cancer metastasis remain ill-defined. Our recent study has demonstrated that TRIM59, an E3 ligase upregulated in metastatic breast cancer, is required for cancer cell survival and metastasis. Genetic depletion of TRIM59 suppresses cancer metastasis by promoting RNFT1-induced K63 polyubiquitination and SQSTM1-directed autophagic degradation of PDCD10, thereby boosting ROCK (Rho associated coiled-coil containing protein kinase)-induced actomyosin contractility and enhancing CDH1-mediated adhesion formation. [ABSTRACT FROM AUTHOR]