Tripartite Motif Containing 37 Research Articles

Design of novel PLK4 inhibitors as TRIM37-amplified breast cancer drugs using 3D-QSAR, molecular docking, and molecular dynamics simulation methods

ABSTRACT A mitosis-associated protein kinase, serine/threonine protein kinase polo-like kinase 4 (PLK4) is thought to be a promising target for the therapy of tripartite motif-containing 37 (TRIM37)-amplified breast cancer. The study's dataset for 3D-QSAR modelling included 37 derivatives of pyrazolo[3,4-d] pyrimidines, and the outcomes showed strong statistical significance (COMFA: q 2 =  0.744, r 2 =  0.997, r pred 2  = 0.702; CoMSIA: q 2 = 0.652, r 2 = 0.991, r pred 2  = 0.722). Findings from an analysis of isopotential maps using the COMFA and COMSIA models, ten novel small molecule inhibitors with potentially high activities were designed. To investigate the processes of interactions among the inhibitor molecules along with the receptor proteins, molecular docking and simulations of molecular dynamics were utilised. According to the results, the amino acids Cys92, Glu96, Asn94, and Asn103 may form hydrogen bonds with the ligands, which could enhance the small molecules’ inhibitory effect. Furthermore, MMPBSA calculations revealed that the newly created compounds have a higher binding affinity to the receptor proteins. Ultimately, these compounds also demonstrated good AMDET properties in pharmacokinetic parameter tests, indicating their promise as innovative medications for the management of breast cancer. These results offer the theoretical direction required to support the creation of effective PLK4 inhibitors.

Abstract 1992: A novel RB1 E3 ligase TRIM37 contributes to palbociclib resistance in breast cancer

Abstract The tripartite motif-containing 37 (TRIM37) is a RING finger E3 ubiquitin ligase and is a poor prognostic factor in breast cancer patients. The gene is located in chromosome 17q23, a region amplified in up to 40% of breast cancers. We observed that activation of androgen receptor (AR) could induce resistance to the CDK4/6 inhibitor Palbociclib, the mechanism yet to be clarified. ChIP-sequencing data suggested that AR binds to the TRIM37 promoter, with AR activation resulting in TRIM37 expression. We hypothesized that TRIM37 might be involved in Palbociclib resistance. Using an ER+ve cell line MCF7 and a TNBC cell line MDA-MB 453, we found that overexpression of TRIM37 could induce Palbociclib resistance. TRIM37 overexpression resulted in RB1 protein downregulation, which is the primary downstream target of CDK4/6, while TRIM37 knockdown enhanced RB1 protein expression. Ubiquitination assay demonstrated TRIM37 overexpression increased the level of RB1 protein ubiquitination. The co-immunoprecipitation (Co-IP) assay confirmed that TRIM37 protein could interact with the RB1 protein. These results suggest that TRIM37 could be the E3 ligase that regulates RB1 degradation. Various deletion mutants of TRIM37 were cloned for Co-IP experiments between these mutants and RB1. Results show that the MATH and c-terminal domains of TRIM37 was the essential region for the interaction. Overexpression of the mutant with the TRIM37 MATH and c-terminal domains (TRIM37-MATH/C) could enhance RB1 protein level. This might be due to competition of TRIM37-MATH/C with wild-type TRIM37 for RB1 binding. Our findings suggest TRIM37 is a novel RB1 E3 ligase, and it binds to the RB1 protein via the MATH and C-terminal domains to regulate protein degradation. Our study also suggests that high expression of TRIM37 mediated by AR activation could deplete RB1, which is the target of Palbociclib, eventually leading to resistance. These findings are supportive of the contribution of AR activation to Palbociclib resistance. Citation Format: Chanping You, Ho Tsoi, Pui Sum Man, Larry Ka Yue Chow, Wei Dai, Ui Soon Khoo. A novel RB1 E3 ligase TRIM37 contributes to palbociclib resistance in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1992.

A multi-platform normalization method for meta-analysis of gene expression data.

Transcriptomic profiling is a mainstay of translational cancer research and is often used to identify cancer subtypes, stratify responders vs. non-responders patients, predict survival, and identify potential targets for therapeutic intervention. Analysis of gene expression data gathered by RNA sequencing (RNA-seq) and microarray is generally the first step in identifying and characterizing cancer-associated molecular determinants. The methodological advancements and reduced costs associated with transcriptomic profiling have increased the number of publicly available gene expression profiles for cancer subtypes. Data integration from multiple datasets is routinely done to increase the number of samples, improve statistical power, and provide better insight into the heterogeneity of the biological determinant. However, utilizing raw data from multiple platforms, species, and sources introduces systematic variations due to noise, batch effects, and biases. As such, the integrated data is mathematically adjusted through normalization, which allows direct comparison of expression measures among studies while minimizing technical and systemic variations. This study applied meta-analysis to multiple independent Affymetrix microarray and Illumina RNA-seq datasets available through the Gene Expression Omnibus (GEO) and The Cancer Gene Atlas (TCGA). We have previously identified a tripartite motif containing 37 (TRIM37), a breast cancer oncogene, that drives tumorigenesis and metastasis in triple-negative breast cancer. In this article, we adapted and assessed the validity of Stouffer's z-score normalization method to interrogate TRIM37 expression across different cancer types using multiple large-scale datasets.

TRIM37 promotes gallbladder cancer proliferation by activating the Wnt/β-catenin pathway via ubiquitination of Axin1

BackgroundGallbladder cancer (GBC) is among the most lethal malignancies in the world, with a prognosis that is extremely poor. The results of previous studies suggest that tripartite motif containing 37 (TRIM37) contributes to the progression of numerous types of cancer. Nevertheless, there is little knowledge about the molecular mechanisms and functions of TRIM37 in GBC. MethodsA clinical significance assessment was conducted on TRIM37 following its detection by immunohistochemistry. In vitro and in vivo functional assays were performed to investigate the role of TRIM37 in GBC. ResultsIn this study, TRIM37 is upregulated in GBC tissues, which is associated with decreased histological differentiation, advanced TNM stage, and shorter overall survival rates. In vitro, TRIM37 knockdown inhibited cell proliferation and promoted apoptosis, and in vivo, TRIM37 knockdown suppressed GBC growth. Contrary to this, cell proliferation is increased in GBC cells when overexpression of TRIM37 is expressed. Mechanistic investigations revealed that TRIM37 promotes GBC progression through activation of the Wnt/β‑catenin signaling pathway via degradation of Axin1. ConclusionThe present study suggests that TRIM37 contributes to the development of GBC and thus provides an important biomarker for predicting GBC prognosis and an effective target for therapeutic intervention.

TRIM37 exacerbates hepatic ischemia/reperfusion injury by facilitating IKKγ translocation

BackgroundHepatic ischemia/reperfusion (I/R) injury is one of the major pathological processes associated with various liver surgeries. However, there is still a lack of strategies to protect against hepatic I/R injury because of the unknown underlying mechanism. The present study aimed to identify a potential strategy and provide a fundamental experimental basis for treating hepatic I/R injury.MethodA classic 70% ischemia/reperfusion injury was established. Immunoprecipitation was used to identify direct interactions between proteins. The expression of proteins from different subcellular localizations was detected by Western blotting. Cell translocation was directly observed by immunofluorescence. HE, TUNEL and ELISA were performed for function tests.ResultWe report that tripartite motif containing 37 (TRIM37) aggravates hepatic I/R injury through the reinforcement of IKK-induced inflammation following dual patterns. Mechanistically, TRIM37 directly interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), inducing K63 ubiquitination and eventually leading to the phosphorylation of IKKβ. TRIM37 enhances the translocation of IKKγ, a regulatory subunit of the IKK complex, from the nucleus to the cytoplasm, thereby stabilizing the cytoplasmic IKK complex and prolonging the duration of inflammation. Inhibition of IKK rescued the function of TRIM37 in vivo and in vitro.ConclusionCollectively, the present study discloses some potential function of TRIM37 in hepatic I/R injury. Targeting TRIM37 might be potential for treatment against hepatic I/R injury.Targeting TRIM37 might be a potential treatment strategy against hepatic I/R injury.Graphical

Metformin inhibits the proliferation and invasion of ovarian cancer cells by suppressing tripartite motif-containing 37-induced tumor necrosis factor receptor-associated factor 2ubiquitination.

Ovarian cancer is the leading cause of death in gynecological malignancies worldwide. Our previous studies have proved that metformin inhibited the proliferation and invasion of ovarian cancer in vitro and in vivo. However, the underlying mechanisms have not been fully elucidated. Immunohistochemistry was carried out to detect the expression of tripartite motif-containing 37 (TRIM37), Ki-67, and MMP-9 in ovarian cancer and normal tissues. The influence of TRIM37 on the proliferation and invasion of ovarian cancer cells was verified by the real-time cellular analysis proliferation test, colony formation test, and Transwell assay. Western blot analysis and immunoprecipitation were used to detect the expression of the nuclear factor-κB (NF-κB) pathway and the interaction between TRIM37 and tumor necrosis factor receptor-associated factor 2 (TRAF2). Ubiquitination detection was carried out to detect the ubiquitination level of TRAF2. The present study revealed that TRIM37 expression was significantly increased in ovarian cancer tissues compared with normal control tissues, and its overexpression was closely associated with proliferation and metastasis. Metformin inhibited the NF-κB signaling pathway by downregulating TRIM37. Metformin also inhibited the ubiquitination of TRAF2 induced by TRIM37 overexpression. Metformin inhibits the proliferation and invasion of ovarian cancer cells by suppressing TRIM37-induced TRAF2 ubiquitination.

TRIM37 promotes the aggressiveness of ovarian cancer cells and increases c-Myc expression by binding to HUWE1

Tripartite motif containing 37 (TRIM37) was reported to function as a tumor promoter in the development of various cancers. However, the biological role of TRIM37 in ovarian cancer (OC) was still unclear. Expressions of TRIM37 and HUWE1 were detected by qRT-PCR and western blotting in OC cells. Cell proliferation was evaluated by CCK-8 assay and colony formation assay. Cell migration and invasion capabilities were examined by wound healing and transwell assay. Flow cytometry and western blotting were performed to measure cell apoptosis. Wnt/β-catenin pathway and the expression of c-Myc were identified by qRT-PCR and western blotting. The binding of TRIM37 and HUWE1 was predicted by STRING database and verified by co-immunoprecipitation. In addition, a xenograft mouse model was established to evaluate the effects of TRIM37 and HUWE1 on tumor growth and c-MYC expression in vivo. The present study revealed that TRIM37 expression was upregulated in OC tissues and cells. TRIM37 silencing inhibited OC cell migration and invasion, promoted OC cell apoptosis, and blocked Wnt/β-catenin signaling pathway, as well as suppressing c-MYC protein expression. Mechanistic studies suggested that TRIM37 binds to HUWE1. HUWE1 was upregulated in OC cells and TRIM37 promoted the c-MYC expression through targeting HUWE1. Animal experiments showed that TRIM37 silencing significantly repressed the tumor growth and c-MYC protein level, but HUWE1 overexpression reversed the effects of TRIM37 knockdown on mice with OC. Our findings revealed that TRIM37 accelerated the progression of OC and promoted c-MYC expression by binding to HUWE1, which provides therapeutic targets for OC treatment.

Modified Yuejuwan Inhibited Cholesterol Accumulation and Inflammation in THP-1 Macrophage-Derived Foam Cells by Inhibiting the Activity of the TRIM37/TRAF2/NF-κB Pathway.

Background This study aimed to explore the function of modified Yuejuwan (MYJ) on THP-1 macrophage-derived foam cells. Methods First, human THP-cells were obtained, and then, grouping was made to the following: control group, foaming group, foaming group +0.2 mg/mL Jiawei Yueju pill, foaming group +0.5 mg/mL Jiawei Yueju pill, and foaming group +1 mg/mL Jiawei Yueju pill. An Oil Red O staining assay was used to examine the uptake of oxidatively modified low-density lipoprotein (oxLDL). The secretion of interleukin (IL)-1β and tumor necrosis factor (TNF)-α were determined using an enzyme-linked immunosorbent assay (ELISA). Real-time quantitative PCR (qRT-PCR) and Western blot were used to quantify genes and proteins expression levels. Results Our results indicated that MYJ inhibited the accumulation of total cholesterol (TC), free cholesterol (FC), and cholesteryl ester (CE) in foam cells. Moreover, the secretion of IL-1β and TNF-α also downregulated in foam cells after treatment of MYJ. Furthermore, we found that tripartite motif-containing 37 (TRIM37) was significantly upregulated in foam cells. Knockdown of TRIM37 promoted cholesterol efflux and presented an anti-inflammation effect in foam cells. Furthermore, TRIM37 positively mediated the translocation of NF-κB to nuclear. It negatively regulated its ubiquitination in foam cells after interacting with TRAF2. Importantly, MYJ profoundly suppressed the function of TRIM37 in foam cells and functioned as a TRIM37 inhibitor. Conclusions This study demonstrated that MYJ might alleviate oxLDL-induced foam cell formation by inhibiting the TRIM37/TRAF2/NF-κB pathway activity. MYJ was a potential agent in preventing atherosclerosis and indicated its potential signaling pathway in foam cells.

TRIM37 Augments AP-2γ Transcriptional Activity and Cellular Localization via K63-linked Ubiquitination to Drive Breast Cancer Progression.

Activator Protein 2 gamma (AP-2γ) is a master transcription factor that plays a critical role in the development and progression of breast cancer. However, the underlying mechanism is still unclear. Herein, using a proteomics approach, we identified Tripartite motif-containing 37 (TRIM37) as a novel coactivator of AP-2γ-mediated transcription in breast cancer cells. We demonstrate that TRIM37 facilitates AP-2γ chromatin binding to directly regulate the AP-2γ mediated transcriptional program. We also show that TRIM37 achieves this by stimulating K63 chain-linked ubiquitination of AP-2γ, promoting protein localization from the cytoplasm to the nucleus. In clinical analyses, we find TRIM37 is upregulated in multiple breast cancer datasets, supporting our findings that the TRIM37-AP-2γ interaction is essential for breast cancer tumor growth. Overall, our work reveals that TRIM37 is an oncogenic coactivator of AP-2γ in breast cancer and provides a novel therapeutic target for treating the disease.

TRIM37 negatively regulates inflammatory responses induced by virus infection via controlling TRAF6 ubiquitination

Virus-induced cytokine storm has been a devastating actuality in clinic. The abnormal production of type I interferon (IFN-1) and upregulation of multiple cytokines induced strong inflammation and thus lead to shock and organ failure. As an E3 ubiquitin ligase, tripartite motif-containing 37 (TRIM37) regulates the ubiquitination of multiple proteins including TRAFs. RNA sequencing was performed to investigated the alteration of transcriptional profile of H1N1-infected patients. qRT-PCR assay was performed to investigate the RNA levels of certain genes. The group of immune cells was examined by the Flow cytometry analysis. H&E staining was applied to evaluate lung inflammation of WT and TRIM37-KO mice. ELISA assay was performed to demonstrate the alteration of multiple cytokines. The protein levels in NF-kB signaling was estimated by western blotting and immunoprecipitation assays were applied to demonstrate the direct interaction between TRIM37 and TRAF-6. The RNA level of TRIM37 decreased in CD11b+ cells of Flu-infected patients. Knockout of TRIM37 inhibited the immune responses of H1N1-infected mice. TRIM37 deficiency reduced the levels of virous proinflammatory cytokines in bone marrow derived macrophages (BMDMs). Mechanically, TRIM37 promoted the K63-linked ubiquitination of TRAF6. TRIM37 negatively regulated inflammatory responses induced by virus infection via promoting TRAF6 ubiquitination at K63.

Circular RNA circRNA_101996 promoted cervical cancer development by regulating miR-1236-3p/TRIM37 axis.

Circular RNAs (circRNAs) appear to be significant modulators in various physiological processes. Recently, it is found that circRNA_101996 exerts important roles in various cancers. Our previous studies showed that circRNA_101996 promoted cervical cancer growth and metastasis by regulating miR-8075/TPX2. However, the potential regulatory role of circRNA_101996 in cervical cancer still needs further investigation. Our results in this study suggested that circRNA_101996 was over-expressed in cervical cancer patients. circRNA_101996 up-regulation remarkably assisted cell proliferation, cell cycle progression, and cell migration in cervical cancer, while circRNA_101996 knockdown exerted the inverse effects. The molecular investigations indicated that circRNA_101996 could increase the expression level of miR-1236-3p, tripartite motif-containing 37 (TRIM37), through binding to miR-1236-3p and reducing its expression. Moreover, in vivo results demonstrated that circRNA_101996 shRNA can function as a tumor suppressor through down-regulating TRIM37 in cervical cancer. In conclusion, our data indicated that circRNA_101996/miR-1236-3p/TRIM37 axis accelerated cervical cancer development, providing novel insights into cervical cancer diagnosis and treatment.

TRIM37 contributes to malignant outcomes and CDDP resistance in gastric cancer.

Background: TRIM37 (Tripartite Motif Containing 37) is an E3 ubiquitin ligase for histone H2A and inhibits transcription in several genes. However, it is not known whether it plays a role in gastric cancer (GC). In this study, we tested whether TRIM37 acts as a cancer-promoting factor by being overexpressed in GC.Methods: We analyzed GC cell lines and 124 primary tumors, which were curatively resected in our hospital between 2001 and 2003.Results: Overexpression of the TRIM37 protein was detected in almost all GC cell lines and GC samples (76 out of 124 cases) and was significantly correlated with lymphatic and venous invasion, advanced T-Stage, N-Stage, histology and high recurrence rate. Patients with TRIM37 overexpressing tumors had a worse survival rate than those with non-expressing tumors (P=0.0057). Moreover, TRIM37 positivity was identified as an independent factor predicting worse outcomes (P=0.018, Hazard ratio 3.41). The apoptotic cell analysis showed that the knockdown of TRIM37 increased apoptosis in comparison with the control. In TRIM37 overexpressing GC cells, knockdown of TRIM37 suppressed the migration and invasion.Conclusions: TRIM37 plays a crucial role in tumor malignant potential through its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.

RETRACTED: LncRNA NEAT1 acts as a key regulator of cell apoptosis and inflammatory response by the miR-944/TRIM37 axis in acute lung injury

Acute lung injury (ALI), a common complication of sepsis, is characterized by the impairment and injury of pulmonary function. The nuclear factor kappa-B (NF-κB) pathway is activated in ALI. Tripartite motif-containing 37 (TRIM37) can activate the NF-κB pathway and is closely associated with inflammation. The purpose of our study is to reveal the role of TRIM37 in ALI. The present study revealed that TRIM37 presented high levels in lung tissues of ALI mice, and knockdown of TRIM37 alleviated lipopolysaccharide (LPS)-induced lung injury, inflammatory response, and cell apoptosis invivo. In addition, knockdown of TRIM37 inhibited the inflammatory response, and cell apoptosis of LPS-treated WI-38cells. Mechanistically, miR-944 was identified to bind with and negatively regulate TRIM37. Furthermore, NEAT1 was indicated to act as a competitive endogenous RNA to promote TRIM37 expression by sequestering miR-944. Detailly, NEAT1 bound with miR-944, negatively modulated miR-944 expression, and positively modulated TRIM37 expression. The rescue assays suggested that overexpression of TRIM37 rescued the influence of NEAT1 knockdown on cell apoptosis and inflammatory response. Overall, NEAT1 facilitated cell apoptosis and inflammatory response of WI-38cells by the miR-944/TRIM37 axis in sepsis-induced ALI, implying that NEAT1 may provide a novel insight for the treatment of sepsis-induced ALI.

Fine-scale estimation of inbreeding rates, runs of homozygosity and genome-wide heterozygosity levels in the Mangalarga Marchador horse breed.

With the availability of high-density SNP panels and the establishment of approaches for characterizing homozygosity and heterozygosity sites, it is possible to access fine-scale information regarding genomes, providing more than just comparisons of different inbreeding coefficients. This is the first study that seeks to access such information for the Mangalarga Marchador (MM) horse breed on a genomic scale. To this end, we aimed to assess inbreeding levels using different coefficients, as well as to characterize homozygous and heterozygous runs in the population. Using Axiom ® Equine Genotyping Array-670k SNP (Thermo Fisher), 192 horses were genotyped. Our results showed different estimates: inbreeding from genomic coefficients (FROH )=0.16; pedigree-based (FPED )=0.008; and a method based on excess homozygosity (FHOM )=0.010. The correlations between the inbreeding coefficients were low to moderate, and some comparisons showed negative correlations, being practically null. In total, 85,295 runs of homozygosity (ROH) and 10,016 runs of heterozygosity (ROHet) were characterized for the 31 horse autosomal chromosomes. The class with the highest percentage of ROH was 0-2Mbps, with 92.78% of the observations. In the ROHet results, only the 0-2 class presented observations, with chromosome 11 highlighted in a region with high genetic variability. Three regions from the ROHet analyses showed genes with known functions: tripartite motif-containing 37 (TRIM37), protein phosphatase, Mg2+ /Mn2+ dependent 1E (PPM1E) and carbonic anhydrase 10 (CA10). Therefore, our findings suggest moderate inbreeding, possibly attributed to breed formation, annulling possible recent inbreeding. Furthermore, regions with high variability in the MM genome were identified (ROHet), associated with the recent selection and important events in the development and performance of MM horses over generations.

ASB16-AS1 up-regulated and phosphorylated TRIM37 to activate NF-κB pathway and promote proliferation, stemness, and cisplatin resistance of gastric cancer.

Long non-coding RNA (lncRNA) ASB16 antisense RNA 1 (ASB16-AS1) is recognized as an oncogene in several cancer types, but its relation to GC is unknown. Tripartite motif containing 37 (TRIM37) has been proven to accelerate the development of gastric cancer (GC), whereas the molecular mechanism assisted ASB16-AS1 and TRIM37 in regulating GC progression remains unclear. Differentially expressed lncRNAs in GC samples were analyzed based on Gene Expression Omnibus (GEO) data. CCK-8 and colony formation assays were applied to determine the proliferative ability of GC cells. Stem cell-like phenotype of GC cells was assessed by sphere formation assay and flow cytometry analysis. Luciferase reporter assay, RNA immunoprecipitation (RIP), pulldown, and co-immunoprecipitation (Co-IP) were performed to verify the interplay of RNA molecules. ASB16-AS1 was upregulated in GC samples according to GEO data and qRT-PCR analysis. ASB16-AS1 strengthened the proliferative ability and stem cell-like characteristics in GC cells. More importantly, ASB16-AS1 encouraged GC cell growth in vivo. Mechanistically, ASB16-AS1 strengthened TRIM37 expression by sequestering miR-3918 and miR-4676-3p. ASB16-AS1 activated NF-kappa B (NF-κB) pathway by cooperating with ATM serine/threonine kinase (ATM) to induce TRIM37 phosphorylation. In summary, ASB16-AS1 exerted oncogenic functions in GC through modulating TRIM37 expression at both mRNA and protein levels.

TRIM37 promotes cell invasion and metastasis by regulating SIP1-mediated epithelial-mesenchymal transition in gastric cancer.

BackgroundTripartite motif containing 37 (TRIM37) has been demonstrated to function importantly during the progression of various cancers. However, the role of TRIM37 in gastric cancer (GC) remains elusive.Materials and methodsTRIM37 mRNA and protein expressions were determined by qRT-PCR, Western blot, and immunohistochemical staining in GC specimens. The effects of TRIM37 on GC cells behavior were evaluated by transwell assays in vitro and metastasis assay in vivo, respectively. Besides, qRT-PCR, Western blot, and immunofluorescence staining were employed to detect the expressions of TRIM37 and epithelial–mesenchymal transition (EMT)-related markers.ResultsThe present study revealed that TRIM37 mRNA or protein expression was significantly increased in GC tissues compared with that in paracancerous control tissues, and its aberrant overexpression was closely associated with clinical metastasis and poor prognosis in patients with GC. TRIM37 knockdown significantly suppressed GC cells migration and invasion in vitro, as well as metastasis in vivo. Inversely, TRIM37 overexpression exerted the opposite effects. Mechanistic studies suggested that SIP1-mediated EMT might be responsible for TRIM37-facilitated GC cells migration and invasion.ConclusionOur findings revealed that high TRIM37 expression was associated with clinical metastasis and poor survival in patients with GC. TRIM37 promoted GC cells migration and invasion via EMT, mediated by the transcription factor SIP1, thus providing a candidate target for GC treatment.

Tripartite motif-containing 37 (TRIM37) promotes the aggressiveness of non-small-cell lung cancer cells by activating the NF-κB pathway.

Non-small-cell lung cancer (NSCLC), in which the NF-κB pathway is constitutively activated, is one of the most common malignancies. Herein, we identify an E3 ubiquitin ligase, tripartite motif-containing 37 (TRIM37), participating in the K63 polyubiquitination of TRAF2, which is a significant step in the activation of NF-κB signaling. Both the mRNA and the protein expression levels of TRIM37 were much higher in NSCLC cell lines and tissues than in normal bronchial epithelial cells and matched adjacent non-tumor tissues. TRIM37 expression correlated closely with clinical stage and poor survival in NSCLC. Overexpression of TRIM37 antagonized cisplatin-induced apoptosis, induced angiogenesis and proliferation, and increased the aggressiveness of NSCLC cells in vitro and in vivo, whereas inhibition of TRIM37 led to the opposite effects. Gene set enrichment analysis (GSEA) showed that TRIM37 expression significantly correlated with NF-κB signaling. Furthermore, we found that TRIM37 bound to TRAF2 and promoted K63-linked ubiquitination of TRAF2, sustaining the eventual activation of the NF-κB pathway. Mutation in the ring finger domain of TRIM37, a hallmark of E3 ubiquitin ligases, led to loss of the ability to promote K63 polyubiquitination of TRAF2 and activate NF-κB signaling. Taken together, our findings provide evidence that TRIM37 plays an important role in constitutive NF-κB pathway activation and could serve as a prognostic factor and therapeutic target in NSCLC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Silencing TRIM37 inhibits the proliferation and migration of non-small cell lung cancer cells.

Tripartite motif containing 37 (TRIM37), a member of the tripartite motif (TRIM) family, has been involved in the development and progression of several tumors. However, its role in non-small cell lung cancer (NSCLC) is still unclear. Therefore, the aim of this study was to investigate the expression pattern and role of TRIM37 in NSCLC. Our results showed that TRIM37 was highly expressed in human NSCLC cell lines. Knockdown of TRIM37 obviously inhibited the proliferation in vitro and xenografted tumor growth in vivo. Furthermore, knockdown of TRIM37 suppressed NSCLC cell migration and invasion by inhibiting the epithelial–mesenchymal transition (EMT) phenotype. Lastly, knockdown of TRIM37 greatly down-regulated the protein expression levels of β-catenin, cyclinD1 and c-myc in A549 cells. In conclusion, the present study revealed that TRIM37 plays an important role in the development and progression of NSCLC. Thus, TRIM37 may act a potential therapeutic target for treating NSCLC.

TRIM37 promotes tumor cell proliferation and drug resistance in pediatric osteosarcoma.

Osteosarcoma (OS) is among the most frequently occurring bone tumors, particularly in children. Clinical treatment of OS is limited due to several factors including resistance to chemotherapy drugs and metastasis, and the underlying molecular mechanisms remain unclear. In the present study, tripartite motif containing 37 (TRIM37) expression levels were upregulated in tumor samples and associated with the development of drug resistance in OS. Furthermore, chemotherapy drug treatment (doxorubicin, cisplatin and methotrexate) induced TRIM37 expression in OS cells in vitro. TRIM37 mRNA and protein were upregulated in 41 pediatric osteosarcoma clinical specimens. To further elucidate the effect of TRIM37, gain and loss-of-function analysis was performed. Overexpression of TRIM37 induced cell proliferation and drug resistance ability of OS cells, whilst TRIM37 knockdown suppressed cell growth rate and restored chemosensitivity. TRIM37-regulated genes were subsequently analyzed by expression microarray and gene set enrichment analysis. Using the Wnt/β-catenin inhibitor XAV-939, the present study demonstrated that TRIM37-induced chemoresistance is partially dependent on the activation of the Wnt/β-catenin signaling pathway. Collectively, the results of the present study suggest that TRIM37 may have a key role in the development of OS and in the ability for the cells to acquire drug resistance, thus it may be a novel target for the treatment of OS.

TRIM37 promotes epithelial‑mesenchymal transition in colorectal cancer.

There is substantial research on the oncogenic role of tripartite motif containing 37 (TRIM37); however, its importance in colorectal cancer (CRC) remains to be elucidated. The present study used reverse transcription-quantitative polymerase chain reaction, immunohistochemistry and western blotting to detect the expression level of TRIM37 in CRC. The importance of TRIM37 in cell proliferation, invasion and metastasis of CRC were investigated through overexpressing or knocking-down of TRIM37 in CRC cell lines, to observe its function. The present study revealed that TRIM37 was overexpressed in human CRC tissues. High TRIM37 expression resulted in increased CRC proliferation, migration and invasion. Mechanistically, it was confirmed that TRIM37 enhanced invasion and metastasis of CRC via the epithelial-mesenchymal transition pathway. In conclusion, the present study suggested that TRIM3 may contribute to CRC and act as a potential therapeutic target for CRC treatment.