TRIM59 deficiency promotes M1 macrophage activation and inhibits colorectal cancer through the STAT1 signaling pathway.

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.

Role of TRIM59 in regulating PPM1A in the pathogenesis of silicosis and the intervention effect of tanshinone IIA.

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.

TRIM59-mediated ferroptosis enhances neuroblastoma development and chemosensitivity through p53 ubiquitination and degradation.

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.

[Effect of TRIM59 Expression Interference on Daunorubicin Chemosensitivity of Chronic Myeloid Leukemia K562 Cells and Its Mechanism].

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/ß-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-3ß protein and the ratio of p-ß-catenin/ß-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-3ß protein and the ratio of p-ß-catenin/ß-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/ß-catenin signaling pathway.

Endoplasmic reticulum-associated SARS-CoV-2 ORF3a elicits heightened cytopathic effects despite robust ER-associated degradation.

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.

A role of TRIM59 in pulmonary hypertension: modulating the protein ubiquitylation modification.

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.

Tripartite motif containing 59 mediates protective anti-oxidative effects in intestinal injury through Nrf2 signaling.

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.

Circ_0006324 regulates cell proliferation, cell-cycle progression, apoptosis, and glycolysis of non-small cell lung cancer cells through miR-496/TRIM59 axis.

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.

TRIM59 attenuates ox-LDL-induced endothelial cell inflammation, apoptosis, and monocyte adhesion through AnxA2.

Background: Atherosclerosis (AS), a chronic inflammatory vascular disease, is a cause of heart attack and ischemic stroke. Tripartite motif-containing protein 59 (TRIM59), a member of the tripartite motif family, has been reported to be involved in inflammatory diseases. This study was to investigate the role of TRIM59 in oxidized low-density lipoprotein (ox-LDL)-induced endothelial cells and examine the mechanism of TRIM59. Methods: To simulate a cellular model of AS in vitro, varying concentrations of ox-LDL (i.e., 20, 40, 60, 80, and 100 µg/mL) were used to treat the human umbilical vein endothelial cells (HUVECs) for 24 h. The messenger ribonucleic acid (RNA) and protein levels of TRIM59, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), and annexin 2 (AnxA2) were examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. The transfection efficacy of overexpression (Ov)-TRIM59 and small-interfering RNA-AnxA2 was examined by RT-qPCR and western blot. Cell counting kit-8 assays, lactate dehydrogenase (LDH) assays, enzyme-linked immunosorbent assays, and terminal-deoxynucleotidyl transferase mediated nick end labeling staining were used to examine viability, LDH expression, inflammation, and apoptosis in HUVECs. The protein levels of B-cell lymphoma 2, Bcl-2-associated X (BAX), cleaved caspase3, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 were assessed by western blot. Additionally, the adhesion of THP-1 to ox-LDL-induced HUVECs was detected using monocyte adhesion assays and the binding of TRIM59 and AnxA2 was verified by co-immunoprecipitation. Results: This study showed that TRIM59 expression was decreased in the ox-LDL-induced HUVECs while LOX-1 expression was increased. After transfection with Ov-TRIM59, TRIM59 in ox-LDL-induced HUVECs was increased, and TRIM59 overexpression alleviated the viability damage, inflammation, and apoptosis of the ox-LDL-induced HUVECs. In addition, THP-1 adhesion to the ox-LDL-induced HUVECs was also suppressed by TRIM59 overexpression. This study also showed that TRIM59 could bind to AnxA2 and promote AnxA2 expression in ox-LDL-stimulated HUVECs. Moreover, the rescue experiments revealed that TRIM59 suppressed the viability damage, inflammation, apoptosis, and monocyte adhesion of the ox-LDL-induced HUVECs via AnxA2. Conclusions: TRIM59 protected against ox-LDL-induced AS by binding to AnxA2.

TRIM59 promotes steatosis and ferroptosis in non-alcoholic fatty liver disease via enhancing GPX4 ubiquitination.

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.

TRIM59 guards ER proteostasis and prevents Bortezomib-mediated colorectal cancer (CRC) cells' killing.

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.

The composition and antiviral activity of scTRIM59 in Mandarin fish.

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.

The role of TRIM59 in immunity and immune-related diseases.

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.

The immune system plays an important role in maintaining physiology. When immune system is in disorder, there are a series of diseases such as allergy, immune deficiency diseases and persistent infections. Immune system is composed of a large number of immune cells, which plays a major role in fighting bacteria, viruses, parasites fungi, or cancer cells. There are many molecules involved in the regulation of immune balance, including TRIM59. Like other TRIM proteins, TRIM59 is important in tumor invasion and metastasis, immune response and thus pathogenesis of various immune diseases. In this study, we summarized the structure and expression regulation of TRIM59, expounded its effect and mechanism on immunity and immune-related diseases, and discussed the possibility of TRIM59 as a therapeutic target.

The role of Tripartite motif containing 59 (TRIM59) in the proliferation and prognosis of intrahepatic cholangiocarcinoma.

Tripartite motif containing 59 (TRIM59) is a crucial gene that is involved in the process of various types of cancer，including breast cancer, lung cancer, colorectal cancer,and so on. Its abnormal expression can affect tumor cell proliferation, metastasis, or apoptosis. In liver cancer, the incidence of intrahepatic cholangiocarcinoma (ICC) is increasing. However, However, it has not been clearly reported on TRIM59 affects the progress of intrahepatic cholangiocarcinoma cells.Firstly, we review the expression of TRIM59 in different cancers and the corresponding normal tissues，and the results preliminarily showed that TRIM59 may be abnormally expressed in many cancers. The author focuses on whether TRIM59 plays a crucial biological role in intrahepatic cholangiocarcinoma. Therefore, we have confirmed through online websites that TRIM59 is highly expressed in intrahepatic cholangiocarcinoma tissues. Furthermore we further found that TRIM59 can be used as an effective prognostic marker for the prognostic guidance of patient survival time. Next, we explore whether the expression level of TRIM59 in intrahepatic cholangiocarcinoma is related to proliferation through the CCK-8 and EDU assay in two ICC cell lines. To further explore how TRIM59 affected the molecular mechanism involved in intrahepatic cholangiocarcinoma cell growth, we found that STAT3 promotes TRIM59 transcription and TRIM59 can affect tumor progression by regulating the PI3K/AKT signaling pathway through luciferase reporter assay and Western blot experiments. In summary, we first found that TRIM59 has great research value in ICC through bioinformatic analysis, then its expression level is closely related to the prognosis through the analysis of clinicopathological indicators of patients with ICC, and the biological mechanism of TRIM59 in ICC provides precise research or therapeutic targets for future cancer treatment. The findings improve our understanding of the potential of TRIM59 in biological functions in ICC and may hold promise as markers for the diagnosis,treatment, and prognosis of ICC. DATA AVAILABILITY: The raw data of this study are derived from the TCGA database, which are publicly available databases.

Evaluation of tripartite motif 59 and its diagnostic utility in benign bowel diseases and colorectal cancer.

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.

Long noncoding RNA LINC01296 regulates the cell proliferation, migration and invasion in neuroblastoma.

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.

D155Y substitution of SARS-CoV-2 ORF3a weakens binding with Caveolin-1.

The clinical manifestation of the recent pandemic COVID-19, caused by the novel SARS-CoV-2 virus, varies from mild to severe respiratory illness. Although environmental, demographic and co-morbidity factors have an impact on the severity of the disease, contribution of the mutations in each of the viral genes towards the degree of severity needs a deeper understanding for designing a better therapeutic approach against COVID-19. Open Reading Frame-3a (ORF3a) protein has been found to be mutated at several positions. In this work, we have studied the effect of one of the most frequently occurring mutants, D155Y of ORF3a protein, found in Indian COVID-19 patients. Using computational simulations we demonstrated that the substitution at 155th changed the amino acids involved in salt bridge formation, hydrogen-bond occupancy, interactome clusters, and the stability of the protein compared with the other substitutions found in Indian patients. Protein-protein docking using HADDOCK analysis revealed that substitution D155Y weakened the binding affinity of ORF3a with caveolin-1 compared with the other substitutions, suggesting its importance in the overall stability of ORF3a-caveolin-1 complex, which may modulate the virulence property of SARS-CoV-2.

TRIM59 promotes osteosarcoma progression via activation of STAT3.

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.

Effects of TRIM59 on RAW264.7 macrophage gene expression and function.

Macrophages have a variety of functions, such as secreting cytokines, phagocytosis, et al. Tripartite motif containing 59 (TRIM59) protein is highly expressed in tumor cells. It can regulate proliferation of tumor cells and promote tumor progression. Recent studies shown that the expression of TRIM59 was different in macrophages when stimulated by different stimuli, however, the effects of TRIM59 on macrophage gene expression profiles and functions are still unknown. In our study, we constructed RAW264.7 macrophages with high and low expression of TRIM59, and used next generation sequencing to explore the effects of TRIM59 on macrophage gene expression profiles. Results showed that TRIM59 affected an abundant number of genes, and may affect phagocytosis and cell cycles. We also examined the expression of surface molecules, secretion of cytokines, phagocytosis, proliferation, and apoptosis of macrophages, and confirmed that TRIM59 increased the expression of FcγRs CD16/32, CD64 and the secretion of TNF-α and IL-10, promoted phagocytosis and proliferation of RAW264.7 cells, inhibited the expression of complement receptor CD11b and antigen presentation related receptors (MHCII, CD80), but TRIM59 had no significant effect on apoptosis. Our study explored the effect of TRIM59 on the gene expression and function of macrophages comprehensively.

[TRIM59 regulates invasion and migration of nasopharyngeal carcinoma cells by targeted modulation of PPM1B].

OBJECTIVE: To investigate whether TRIM59 regulates invasion and metastasis of nasopharyngeal carcinoma cells by targeting PPM1B. METHOD: We analyzed the expression of TRIM59 in nasopharyngeal carcinoma tissues based on data from TCGA database and detected the expressions of TRIM59 and PPM1B in nasopharyngeal carcinoma and adjacent tissues using Western blotting. We also detected the expressions of TRIM59 and PPM1B at both the mRNA and protein levels in nasopharyngeal carcinoma cell lines using RT-PCR and Western blotting. Stable cell lines with TRIM59 overexpression or knockdown were established in HNE1 cells, in which the targeting relationship between TRIM59 and PPM1B was analyzed using Western blotting and a luciferase reporter gene assay. Transwell chamber assay was used to assess changes in the invasion and migration abilities of HNE1 cells with TRIM59 overexpression or knockdown. RESULTS: Analysis based on TCGA database showed that TRIM59 expression was significantly higher in nasopharyngeal carcinoma tissues than in adjacent tissues (P=0.006); the expression of TRIM59 increased (P=0.01) and PPM1B expression decreased significantly (P=0.03) in nasopharyngeal carcinoma tissues. Compared with HNEpC cells, HNE1 cells expressed a significantly higher level of TRIM59 (P=0.04) but a lower level of PPM1B (P=0.01). Luciferase reporter gene assay indicated that PPM1B was a downstream target gene of TRIM59 and its expression was negatively correlated with TRIM59 expression (P=0.01). In HNE1 cells, TRIM59 overexpression significantly promoted cell invasion (P=0.01) and migration (P=0.02) while TRIM59 knockdown obviously suppressed cell invasion (P=0.01) and migration (P=0.01). TRIM59 knockdown with simultaneous PPM1B overexpression more strongly inhibited invasion (P=0.02) and migration (P=0.01) of HNE1 cells as compared with TRIM59 knockdown alone. CONCLUSION: TRIM59 regulates invasion and migration of nasopharyngeal carcinoma cells through targeted modulation of PPM1B.