Nanobubble-mediated co-delivery of siTRIM37 and IR780 for gene and sonodynamic combination therapy against triple negative breast cancer.

Gene therapy often fails due to enzyme degradation and low transfection efficiency, and single gene therapy usually cannot completely kill tumor cells. Several studies have reported that tripartite motif-containing protein 37 (TRIM37) plays a significant role in promoting the occurrence and development of triple negative breast cancer (TNBC). Herein, we constructed siTRIM37 and IR780 co-loaded nanobubbles (NBs) to achieve the combination of gene therapy and sonodynamic therapy (SDT) against TNBC. On the one hand, ultrasound irradiation causes siRNA@IR780 NBs rupture to produce ultrasound targeted NB destruction effect, which promotes the entry of IR780 and siTRIM37 into cells, increasing the local concentration of IR780 and gene transfection efficiency. On the other hand, under the stimulation of ultrasound, IR780 generates reactive oxygen species to kill TNBC cells. Mechanism studies reveal that TRIM37 is an anti-apoptotic gene in TNBC, and inhibiting TRIM37 expression can induce cell death through the apoptotic pathway. And the combination of siTRIM37 and SDT can aggravate the degree of apoptosis to increase cell death. Therefore, siRNA@IR780 NBs-mediated combination therapy may provide a new treatment approach for TNBC in the future.

A proteomic study of the downregulation of TRIM37 on chondrocytes: Implications for the MULIBREY syndrome.

MULIBREY nanism which results from autosomal recessive mutations in TRIM37 impacts skeletal development, leading to growth delay with complications in multiple organs. In this study, we employed a combined proteomics and qPCR screening approach to investigate the molecular alterations in the CHON-002 cell line by comparing CHON-002 wild-type (WT) cells to CHON-002 TRIM37 knockdown (KD) cells. Our proteomic analysis demonstrated that TRIM37 depletion predominantly affects the expression of extracellular matrix proteins (ECM). Specifically, nanoLC-MS/MS experiments revealed an upregulation of SPARC, and collagen products (COL1A1, COL3A1, COL5A1) in response to TRIM37 KD. Concurrently, large-scale qPCR assays targeting osteogenesis-related genes corroborated these dysregulations of SPARC at the mRNA level. Gene ontology enrichment analysis highlighted the involvement of dysregulated proteins in ECM organization and TGF-ß signaling pathways, indicating a role for TRIM37 in maintaining ECM integrity and regulating chondrocyte proliferation. These findings suggest that TRIM37 deficiency in chondrocytes change ECM protein composition and could impairs long bone growth, contributing to the pathophysiology of MULIBREY nanism.

TRIM37 interacts with EZH2 to epigenetically suppress PTCH1 and regulate stemness in glioma stem cells through sonic hedgehog pathway.

BACKGROUND: Glioma stem cells (GSCs), which are known for their therapy resistance, play a substantial role in treatment inefficacy for glioblastoma multiforme (GBM). TRIM37, a member of the tripartite motif (TRIM) protein family initially linked to a rare growth disorder, has been recognized for its oncogenic role. However, the mechanism by which TRIM37 regulates tumor growth in glioma and GSCs is unclear. METHODS: For the in vitro experiments, gene expression was measured by western blotting, RT-qPCR, and immunofluorescence. Cell viability was detected by CCK-8, and cell apoptosis was detected by flow cytometry. The interaction between Enhancer of Zeste Homolog 2 (EZH2) and TRIM37 was verified by co-immunoprecipitation (Co-IP). The interaction between EZH2 and the PTCH1 promoter was verified using dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP). For the in vivo experiments, an orthotopically implanted glioma mouse model was used to validate tumor growth. RESULTS: The expression of TRIM37 is higher in GSCs compared with matched non-GSCs. TRIM37 knockdown promotes apoptosis, decreased stemness in GSCs, and reduces tumor growth in GSCs xenografts of nude mice. TRIM37 and EZH2 co-localize in the nucleus and interact with each other. TRIM37 knockdown or EZH2 inhibition downregulates the protein expressions associated with the Sonic Hedgehog (SHH) pathway. EZH2 epigenetically downregulates PTCH1 to activate SHH pathway in GSCs. CONCLUSIONS: TRIM37 maintains the cell growth and stemness in GSCs through the interaction with EZH2. EZH2 activates SHH stem cell signaling pathway by downregulating the expression of SHH pathway suppressor PTCH1. Our findings suggest that TRIM37 may be a potential therapeutic target for GBM.

LncRNA HOXC-AS3 accelerates malignant proliferation of cervical cancer cells via stabilizing KDM5B.

BACKGROUND: Cervical cancer (CC) is a common malignancy amongst women globally. Ubiquitination plays a dual role in the occurrence and development of cancers. This study analyzed the mechanism of long noncoding RNA HOXC cluster antisense RNA 3 (lncRNA HOXC-AS3) in malignant proliferation of CC cells via mediating ubiquitination of lysine demethylase 5B (KDM5B/JARID1B). METHODS: The expression patterns of lncRNA HOXC-AS3 and KDM5B were measured by real-time quantitative polymerase chain reaction or Western blot analysis. After transfection with lncRNA HOXC-AS3 siRNA and pcDNA3.1-KDM5B, proliferation of CC cells was assessed by the cell counting kit-8, colony formation, and 5-Ethynyl-2'-deoxyuridine staining assays. The xenograft tumor model was established to confirm the impact of lncRNA HOXC-AS3 on CC cell proliferation in vivo by measuring tumor size and weight and the immunohistochemistry assay. The subcellular location of lncRNA HOXC-AS3 and the binding of lncRNA HOXC-AS3 to KDM5B were analyzed. After treatment of lncRNA HOXC-AS3 siRNA or MG132, the protein and ubiquitination levels of KDM5B were determined. Thereafter, the interaction and the subcellular co-location of tripartite motif-containing 37 (TRIM37) and KDM5B were analyzed by the co-immunoprecipitation and immunofluorescence assays. RESULTS: LncRNA HOXC-AS3 and KDM5B were upregulated in CC tissues and cells. Depletion of lncRNA HOXC-AS3 repressed CC cell proliferation and in vivo tumor growth. Mechanically, lncRNA HOXC-AS3 located in the nucleus directly bound to KDM5B, inhibited TRIM37-mediated ubiquitination of KDM5B, and upregulated the protein levels of KDM5B. KDM5B overexpression attenuated the inhibitory role of silencing lncRNA HOXC-AS3 in CC cell proliferation in vivo and in vitro. CONCLUSION: Nucleus-located lncRNA HOXC-AS3 facilitated malignant proliferation of CC cells via stabilization of KDM5B protein levels.

The role of hepatitis B virus surface protein in inducing Sertoli cell ferroptosis.

BACKGROUNDS: Hepatitis B virus infection could result in male infertility with sperm defects and dysfunction. Sertoli cells are essential for testis function and play a crucial role in spermatogenesis. Sertoli cell death contributes to spermatogenesis impairment, leading to poor sperm quality. Ferroptosis has been implicated as a mechanism of Sertoli cell death. The issue in studying the relationship between hepatitis B virus and Sertoli cell ferroptosis has not yet been addressed. OBJECTIVES: To explore the mechanisms underlying ferroptosis in hepatitis B virus-exposed Sertoli cells. MATERIALS AND METHODS: Human Sertoli cells were treated in vitro with levels of 25, 50, and 100 µg/mL of hepatitis B virus surface protein (HBs). Cell viability and levels of glutathione, malondialdehyde, cellular ferrous ion (Fe2+ ), lipid peroxidation, and N6-methyladenosine in Sertoli cells were detected. The level of glutathione peroxidase 4, transferrin receptor 1, ferritin heavy chain, tripartite motif (TRIM) 37, methyltransferase like 3, and insulin-like growth factor 2 mRNA binding protein 2 was examined. Cell transfection was carried out to alter expression of ferroptosis-related proteins. qPCR and immunoblotting were performed to measure protein expression level. Immunoprecipitation was applied to determine the protein and protein-RNA interaction. Luminescence analysis was performed to identify the target of methyltransferase like 3. RESULTS: HBs exposure triggered ferroptosis featured with increased intracellular Fe2+ ion, reduced cell viability and expression of glutathione peroxidase 4 in Sertoli cells. HBs treatment significantly increased TRIM37 expression, which suppressed glutathione peroxidase 4 expression through ubiquitination. TRIM37 silencing attenuated the effect of HBs exposure-regulated cell viability and ferroptosis. HBs upregulated N6-methyladenosine modification in TRIM37 3'-UTR by increasing methyltransferase like 3 expression. The binding of N6-methyladenosine reader insulin-like growth factor 2 mRNA binding protein 2 and TRIM37 3'-UTR enhanced the stability of TRIM37 mRNA. CONCLUSION: HBs can decrease human Sertoli cell viability by promoting ferroptosis induced by the loss of glutathione peroxidase 4 activity through TRIM37-mediated ubiquitination of glutathione peroxidase 4. The findings highlight the role of TRIM37/glutathione peroxidase 4 signaling responsible for ferroptosis regulation in hepatitis B virus-infected Sertoli cells.

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/ß-catenin pathway via ubiquitination of Axin1.

BACKGROUND: Gallbladder 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. METHODS: A 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. RESULTS: In 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/ß­catenin signaling pathway via degradation of Axin1. CONCLUSION: The 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.

BACKGROUND: Hepatic 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. METHOD: A 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. RESULT: We 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 IKKß. 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. CONCLUSION: Collectively, 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.

Aerobic glycolysis and tumor progression of hepatocellular carcinoma are mediated by ubiquitin of P53 K48-linked regulated by TRIM37.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer in the world. In malignant liver cancer, the increase of aerobic glycolysis indicates that the possibility of tumorigenesis is greatly enhanced. TRIM37 is a member of the TRIM family of proteins that possesses E3 ubiquitin ligase activity and has been implicated in the occurrence and prognosis of many different tumors. However, the stability of P53 plays an important role in preventing tumorigenesis. The mechanism by which TRIM37 regulates the stability of P53 through ubiquitin in the progression of hepatocellular carcinoma is still unclear. MATERIALS AND METHODS: Real-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the expression of mRNA and protein in HCC cells. Lactic acid production, glucose uptake, and ATP levels were measured by BioVision kit. The following were used to assess the in vitro function of TRIM37 in HCC cells: cell counting kit-8 (CCK-8), colony formation assay, cell migration and invasion assay, and flow cytometry. We observed the effect of TRIM37 on the growth of transplanted tumors in nude mice. Co-Immunoprecipitation (Co-IP) revealed a binding relationship between TRIM37 and P53. RESULTS: The expression of TRIM37 in hepatocellular carcinoma (HCC) tissues was higher than that of normal tissues according to an analysis of The Cancer Genome Atlas (TCGA) database.Loss-of-function assays indicated that TRIM37 inhibited the proliferation, colony formation, migration, and invasion of liver cancer cells. The mechanism is as follows: TRIM37 interacts with the P53 protein to induce E3 ligase activity, ubiquitination, and degradation, further promoting the malignant characteristics of hepatocellular carcinoma, thus promoting the process of glycolysis. Genetic knockdown of P53 reversed the promoting function of TRIM37 on the growth and metastasis of hepatocellular carcinoma cells. CONCLUSIONS: Our study showed that the TRIM37-P53 axis plays a role in the progression of liver cancer, and thus is a potential target for the treatment of liver cancer.

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

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 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.

Global cellular response to chemical perturbation of PLK4 activity and abnormal centrosome number.

Centrosomes act as the main microtubule organizing center (MTOC) in metazoans. Centrosome number is tightly regulated by limiting centriole duplication to a single round per cell cycle. This control is achieved by multiple mechanisms, including the regulation of the protein kinase PLK4, the most upstream facilitator of centriole duplication. Altered centrosome numbers in mouse and human cells cause p53-dependent growth arrest through poorly defined mechanisms. Recent work has shown that the E3 ligase TRIM37 is required for cell cycle arrest in acentrosomal cells. To gain additional insights into this process, we undertook a series of genome-wide CRISPR/Cas9 screens to identify factors important for growth arrest triggered by treatment with centrinone B, a selective PLK4 inhibitor. We found that TRIM37 is a key mediator of growth arrest after partial or full PLK4 inhibition. Interestingly, PLK4 cellular mobility decreased in a dose-dependent manner after centrinone B treatment. In contrast to recent work, we found that growth arrest after PLK4 inhibition correlated better with PLK4 activity than with mitotic length or centrosome number. These data provide insights into the global response to changes in centrosome number and PLK4 activity and extend the role for TRIM37 in regulating the abundance, localization, and function of centrosome proteins.

Design, synthesis, and biological evaluation of novel pyrazolo [3,4-d]pyrimidine derivatives as potent PLK4 inhibitors for the treatment of TRIM37-amplified breast cancer.

Serine/threonine-protein kinase polo-like kinase 4 (PLK4) is a mitosis-associated protein kinase that plays a vital role in the duplication of centrioles in dividing cells and is considered a promising target of synthetic lethality in TRIM37-amplified breast cancer. Herein, based on a rational drug design strategy, we described a series of pyrazolo [3,4-d]pyrimidine derivatives as potent PLK4 inhibitors and dissected the relevant structure-activity relationships (SARs). Most compounds showed potent suppressive activities against PLK4, with IC50 values of < 10 nM. Among them, compound 24j (PLK4 IC50 = 0.2 nM) displayed potent enzyme inhibition and good selectivity in a panel of 35 kinases. At the cellular level, compound 24j exhibited notable antiproliferative activities against MCF-7, BT474, and MDA-MB-231 cells, with IC50 values of 0.36, 1.35, and 2.88 µM, respectively. Compound 24j killed TRIM37-amplified breast cancer cells. Moreover, we evaluated the clone formation, proliferation, cycle arrest, and migration abilities of compound 24j using MCF-7 cells. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound 24j showed remarkable plasma stability, moderate liver microsomal stability, and weak inhibitory activity against the main subtypes of human cytochrome P450. Based on in vivo pharmacokinetic studies in Sprague Dawley rats, compound 24j exhibited a relatively high plasma clearance and a low F value (8.03%). Overall, these results support the further development of compound 24j as a potential lead compound to treat TRIM37-amplified breast cancer.

Mechanism of RNA-binding protein Lin28 in neuronal ferroptosis after intracerebral haemorrhage.

Intracerebral haemorrhage (ICH) is a highly risky cerebrovascular disease with poor prognosis. Lin-28 homolog A (Lin28) has been identified as a crucial regulator in ICH. This study aims to analyse the mechanism of Lin28 in neuronal ferroptosis after ICH and provide theoretical basis for ICH treatment. An ICH mouse model was established via injection of collagenase VII, followed by neurological impairment assessment, and haematoxylin-eosin staining. An in vitro ICH model was established using hemin treatment. Next, cell viability and ferroptosis parameters were detected via cell counting kit-8, assay kits, enzyme-linked immunosorbent assay and western blot. Lin28 expression and tripartite motif-containing 37 (Trim37) mRNA level were detected via western blot and quantitative real-time polymerase chain reaction (qRT-PCR). The binding relationship of Lin28 and Trim37 was verified. ICH mice exhibited neuronal ferroptosis and upregulation of Lin28. Lin28 inhibition alleviated neurological impairment, manifested by decreased hematoma, oedema, neuronal necrosis, glial cell swelling, intracellular vacuoles and inflammatory cell infiltration, reduced Fe2+ concentration and reactive oxygen species content, and increased glutathione and glutathione peroxidase 4 activity. In the hemin-induced HT-22 cells, Lin28 inhibition promoted cell viability and alleviated neuronal ferroptosis. Lin28 bound to Trim37 mRNA to stabilize the mRNA level of Trim37. Overexpression of Trim37 reversed the alleviating role of silencing Lin28 in neuronal ferroptosis after ICH. Overall, Lin28 stabilized the mRNA level of Trim37 to aggravate neuronal ferroptosis after ICH.

TRIM37 Promotes Pancreatic Cancer Progression through Modulation of Cell Growth, Migration, Invasion, and Tumor Immune Microenvironment.

TRIM37 dysregulation has been observed in several cancer types, implicating its possible role in tumorigenesis. However, the role of TRIM37 in pancreatic cancer progression remains unclear. In the present study, we observed that TRIM37 knockdown resulted in reduced proliferation, clonogenicity, migration, and invasion ability of pancreatic cancer cells. Furthermore, an in vivo study using an orthotopic syngeneic animal model further confirmed that reduced expression of TRIM37 in cancer cells suppressed tumor growth in vivo. Moreover, in mice bearing TRIM37 knockdown pancreatic cancer cells, the proportion of CD11b+F4/80+MHCIIlow immunosuppressive macrophages was significantly reduced in tumor milieu, which might be due to the regulatory role of TRIM37 in cytokine production by pancreatic cancer cells. Collectively, these findings suggest a key role of TRIM37 in promoting pancreatic cancer progression.

Liver pathology and biochemistry in patients with mutations in TRIM37 gene (Mulibrey nanism).

BACKGROUND AND AIMS: Mulibrey nanism (MUL) is a multiorgan disease caused by recessive mutations in the TRIM37 gene. Chronic heart failure and hepatopathy are major determinants of prognosis in MUL patients, which prompted us to study liver biochemistry and pathology in a national cohort of MUL patients. METHODS: Clinical, laboratory and imaging data were collected in a cross-sectional survey and retrospectively from hospital records. Liver histology and immunohistochemistry for 10 biomarkers were assessed. RESULTS: Twenty-one MUL patients (age 1-51 years) with tumour suspicion showed moderate congestion, steatosis and fibrosis in liver biopsies and marginally elevated levels of serum GGT, AST, ALT and AST to platelet ratio index (APRI) in 20%-66%. Similarly, GGT, AST, ALT and APRI levels were moderately elevated in 12%-69% of 17 MUL patients prior to pericardiectomy. In a cross-sectional evaluation of 36 MUL outpatients, GGT, total bilirubin and galactose half-life (Gal½) correlated with age (r = 0.45, p = .017; r = 0.512, p = .007; r = 0.44, p = .03 respectively). The frequency of clearly abnormal serum values of 15 parameters analysed, however, was low even in patients with signs of restrictive cardiomyopathy. Transient elastography (TE) of the liver revealed elevated levels in 50% of patients with signs of heart failure and TE levels correlated with several biochemistry parameters. Biomarkers of fibrosis, sinusoidal capillarization and hepatocyte metaplasia showed increased expression in autopsy liver samples from 15 MUL patients. CONCLUSION: Liver disease in MUL patients was characterized by sinusoidal dilatation, steatosis and fibrosis with individual progression to cirrhosis and moderate association of histology with cardiac function, liver biochemistry and elastography.

Increased alveolar epithelial TRAF6 via autophagy-dependent TRIM37 degradation mediates particulate matter-induced lung metastasis.

Epidemiological and clinical studies have shown that exposure to particulate matter (PM) is associated with an increased incidence of lung cancer and metastasis. However, the underlying mechanism remains unclear. Here, we demonstrated the central role of PM-induced neutrophil recruitment in promoting lung cancer metastasis. We found that reactive oxygen species (ROS)-mediated alveolar epithelial macroautophagy/autophagy was essential for initiating neutrophil chemotaxis and pre-metastatic niche formation in the lungs in response to PM exposure. During PM-induced autophagy, the E3 ubiquitin ligase TRIM37 was degraded and protected TRAF6 from proteasomal degradation in lung epithelial cells, which promoted the NFKB-dependent production of chemokines to recruit neutrophils. Importantly, ROS blockade, autophagy inhibition or TRAF6 knockdown abolished PM-induced neutrophil recruitment and lung metastasis enhancement. Our study indicates that host lung epithelial cells and neutrophils coordinate to promote cancer metastasis to the lungs in response to PM exposure and provides ideal therapeutic targets for metastatic progression.Abbreviations: ACTA2/α-SMA: actin alpha 2, smooth muscle, aorta; ATII: alveolar type II; Cho-Traf6 siRNA: 5'-cholesterol-Traf6 siRNA; EMT: epithelial-mesenchymal transition; HBE: human bronchial epithelial; HCQ: hydroxychloroquine; MAPK: mitogen-activated protein kinase; NAC: N-acetyl-L-cysteine; NFKB: nuclear factor of kappa light polypeptide gene enhancer in B cells; NS: normal saline; PM: particulate matter; ROS: reactive oxygen species; TRAF6: TNF receptor-associated factor 6; TRIM37: tripartite motif-containing 37.

Whole Exome Sequencing Identified the Causative Mutation in a 4-Year-Old Female with Mulibrey Nanism: A Case Report.

Mulibrey Nanism is a rare multisystem disorder inherited in an autosomal recessive manner caused by mutations in the TRIM37 gene. Most of the reported cases are from Finland, but this condition has rarely occurred in other countries. Although the clinical diagnosis of Mulibrey nanism is a challenge during the first months of life, the disease can be suspected clinically due to the distinctive features of the patients. A 4-year-old female with pneumonia, cardiomyopathy, growth retardation, peripheral edema, and characteristic craniofacial features was referred to Tehran Hope Generation Foundation Genetic diagnosis Center, in October 2021. Genomic DNA was isolated from peripheral blood samples of the patient and her parents and Whole exome sequencing was performed for the patient. Whole exome sequencing revealed a homozygous G>A splice site variant (TRIM37; c.370-1G>A). Sanger sequencing confirmed the segregation of the variant with phenotype in this family. Whole exome sequencing can be helpful in the diagnosis of the patients suspecting to Mulibrey nanism and lacking sufficient clinical presentation according to the diagnostic algorithm.

TRIM37 interacts with PTEN to promote the growth of human T-cell acute lymphocytic leukemia cells through regulating PI3K/AKT pathway.

Background: TRIM37 has been reported to be associated with the tumorigenesis of cancers. However, the role of TRIM37 in T-cell acute lymphoblastic leukemia (T-ALL) remains unclear. This study aimed to characterize the effect of TRIM37 on T-ALL. Methods: TRIM37 expression in T-ALL patients and T-ALL cell lines was determined by qRT-PCR and Western blot. Knockdown or overexpression of TRIM37 was conducted by transferring small-interfering TRIM37 or lentivirus-mediated transducing into T-ALL cells. CCK-8 assay and flow cytometry assay were conducted to analyze the proliferation and apoptosis of T-ALL cells. Co-immunoprecipitation experiments were conducted to investigate the relationship between TRIM37 and PTEN and the ubiquitination of PTEN. Results: Our results suggested that TRIM37 expression was upregulated in the blood of T-ALL patients and T-ALL cell lines. Knockdown of TRIM37 noticeably inhibited the proliferation and promoted apoptosis of T-ALL cells. Ectopic expression of TRIM37 promoted the proliferation and suppressed the apoptosis rate of MOLT-4 cells and enhanced the phosphorylation of AKT. Moreover, TRIM37 interacted with PTEN and accelerated the degradation of PTEN via TRIM37-mediated ubiquitination in T-ALL cells. Moreover, TRIM37 reduced the sensitivity of T-ALL cells to bortezomib treatment. Additionally, PI3K/AKT signaling pathway was involved in the function of TRIM37 in T-ALL. TRIM37 contributed to the proliferation of T-ALL cells and reduced the susceptibility of T-ALL cells to bortezomib treatment through ubiquitination of PTEN and activating PI3K/AKT signaling pathway. Conclusions: Our study suggested that TRIM37 could be considered as a therapeutic target for T-ALL.

miR-942-5p prevents sepsis-induced acute lung injury via targeting TRIM37.

MicroRNAs (miRNAs) have been demonstrated to play pivotal roles in the pathogenesis of sepsis-induced acute lung injury (ALI). In this work, we aimed to clarify the potential role and the underlying mechanism of miR-942-5p in a lipopolysaccharide (LPS)-induced A549 cell injury model. The cell injury was evaluated by CCK-8 assay, flow cytometry and enzyme-linked immunosorbent assay (ELISA). The expression levels of miR-942-5p and tripartite motif-containing protein 37 (TRIM37) were measured by real-time PCR and Western blot, and their association was then validated by bioinformatics, luciferase reporter assay and RNA pull-down assay. We found that the expression of miR-942-5p was decreased in LPS-treated A549 cells. Furthermore, LPS treatment suppressed A549 cell viability, promoted apoptosis and increased the levels of inflammatory cytokines. Conversely, overexpression of miR-942-5p increased cell viability, reduced apoptosis and alleviated inflammatory cytokine secretion in the presence of LPS. Moreover, miR-942-5p directly targeted TRIM37 by binding to the 3'-UTR of TRIM37 mRNA. Upregulation of TRIM37 effectively reversed the anti-apoptotic and anti-inflammatory effects of miR-942-5p in LPS-induced A549 cells. Our findings suggested that miR-942-5p protected against LPS-induced cell injury through inhibiting apoptosis and inflammation in A549 cells by negatively regulating TRIM37.