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Long mammalian introns make it challenging for the RNA processing machinery to identify exons accurately. We find that LINE-derived sequences (LINEs) contribute to this selection by recruiting dozens of RNA-binding proteins (RBPs) to introns. This includes MATR3, which promotes binding of PTBP1 to multivalent binding sites within LINEs. Both RBPs repress splicing and 3' end processing within and around LINEs. Notably, repressive RBPs preferentially bind to evolutionarily young LINEs, which are located far from exons. These RBPs insulate the LINEs and the surrounding intronic regions from RNA processing. Upon evolutionary divergence, changes in RNA motifs within LINEs lead to gradual loss of their insulation. Hence, older LINEs are located closer to exons, are a common source of tissue-specific exons, and increasingly bind to RBPs that enhance RNA processing. Thus, LINEs are hubs for the assembly of repressive RBPs and also contribute to the evolution of new, lineage-specific transcripts in mammals. VIDEO ABSTRACT.
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Ribonucleoproteínas Nucleares Heterogêneas/química , Elementos Nucleotídeos Longos e Dispersos , Proteínas Associadas à Matriz Nuclear/química , Poliadenilação , Proteína de Ligação a Regiões Ricas em Polipirimidinas/química , Proteínas de Ligação a RNA/química , RNA/química , Processamento Alternativo , Animais , Sítios de Ligação , Éxons , Células HeLa , Humanos , Íntrons , Camundongos , Mutação , Motivos de Nucleotídeos , Filogenia , Ligação Proteica , Mapeamento de Interação de Proteínas , Splicing de RNARESUMO
Long interspersed nuclear elements (LINEs) play essential roles in shaping chromatin states, while the factors that cooperate with LINEs and their roles in higher-order chromatin organization remain poorly understood. Here, we show that MATR3, a nuclear matrix protein, interplays with antisense LINE1 (AS L1) RNAs to form a meshwork via phase separation, providing a dynamic platform for chromatin spatial organization. MATR3 and AS L1 RNAs affect the nuclear localization of each other. After MATR3 depletion, the chromatin, particularly H3K27me3-modified chromatin, redistributes in the cell nuclei. Topologically associating domains (TADs) that highly transcribe MATR3-associated AS L1 RNAs show decreased intra-TAD interactions in both AML12 and ES cells. MATR3 depletion increases the accessibility of H3K27me3 domains adjacent to MATR3-associated AS L1, without affecting H3K27me3 modifications. Furthermore, amyotrophic lateral sclerosis (ALS)-associated MATR3 mutants alter biophysical features of the MATR3-AS L1 RNA meshwork and cause an abnormal H3K27me3 staining. Collectively, we reveal a role of the meshwork formed by MATR3 and AS L1 RNAs in gathering chromatin in the nucleus.
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Esclerose Lateral Amiotrófica , RNA Antissenso , Humanos , Histonas/genética , Esclerose Lateral Amiotrófica/genética , Cromatina/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas Associadas à Matriz Nuclear/genética , Proteínas Associadas à Matriz Nuclear/metabolismoRESUMO
BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with higher aggressiveness and poorer outcomes. Recently, long non-coding RNAs (lncRNAs) have become the crucial gene regulators in the progression of human cancers. However, the function and underlying mechanisms of lncRNAs in TNBC remains unclear. METHODS: Based on public databases and bioinformatics analyses, the low expression of lncRNA MIDEAS-AS1 in breast cancer tissues was detected and further validated in a cohort of TNBC tissues. The effects of MIDEAS-AS1 on proliferation, migration, invasion were determined by in vitro and in vivo experiments. RNA pull-down assay and RNA immunoprecipitation (RIP) assay were carried out to reveal the interaction between MIDEAS-AS1 and MATR3. Luciferase reporter assay, Chromatin immunoprecipitation (ChIP) and qRT-PCR were used to evaluate the regulatory effect of MIDEAS-AS1/MATR3 complex on NCALD. RESULTS: LncRNA MIDEAS-AS1 was significantly downregulated in TNBC, which was correlated with poor overall survival (OS) and progression-free survival (PFS) in TNBC patients. MIDEAS-AS1 overexpression remarkably inhibited tumor growth and metastasis in vitro and in vivo. Mechanistically, MIDEAS-AS1 mainly located in the nucleus and interacted with the nuclear protein MATR3. Meanwhile, NCALD was selected as the downstream target, which was transcriptionally regulated by MIDEAS-AS1/MATR3 complex and further inactivated NF-κB signaling pathway. Furthermore, rescue experiment showed that the suppression of cell malignant phenotype caused by MIDEAS-AS1 overexpression could be reversed by inhibition of NCALD. CONCLUSIONS: Collectively, our results demonstrate that MIDEAS-AS1 serves as a tumor-suppressor in TNBC through modulating MATR3/NCALD axis, and MIDEAS-AS1 may function as a prognostic biomarker for TNBC.
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MicroRNAs , Neurocalcina , RNA Longo não Codificante , Neoplasias de Mama Triplo Negativas , Humanos , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neurocalcina/genética , Neurocalcina/metabolismo , Proteínas Associadas à Matriz Nuclear/genética , Proteínas Associadas à Matriz Nuclear/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Matrin 3 is a nuclear matrix protein that has many roles in RNA processing including splicing and transport of mRNA. Many missense mutations in the Matrin 3 gene (MATR3) have been linked to familial forms of amyotrophic lateral sclerosis (ALS) and distal myopathy. However, the exact role of MATR3 mutations in ALS and myopathy pathogenesis is not understood. To demonstrate a role of MATR3 mutations in vivo, we generated a novel CRISPR/Cas9 mediated knock-in mouse model harboring the MATR3 P154S mutation expressed under the control of the endogenous promoter. The P154S variant of the MATR3 gene has been linked to familial forms of ALS. Heterozygous and homozygous MATR3 P154S knock-in mice did not develop progressive motor deficits compared to wild-type mice. In addition, ALS-like pathology did not develop in nervous or muscle tissue in either heterozygous or homozygous mice. Our results suggest that the MATR3 P154S variant is not sufficient to produce ALS-like pathology in vivo.
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Esclerose Lateral Amiotrófica , Proteínas Associadas à Matriz Nuclear , Animais , Camundongos , Esclerose Lateral Amiotrófica/metabolismo , Músculos/metabolismo , Doenças Musculares/genética , Mutação , Mutação de Sentido Incorreto , Proteínas Associadas à Matriz Nuclear/genética , Proteínas Associadas à Matriz Nuclear/metabolismoRESUMO
The F115C mutation in the MATR3 gene has been linked to amyotrophic lateral sclerosis (ALS). To determine the pathogenicity of the F115C mutation and the mechanism by which this mutation causes ALS, we generated mice that harbor the F115C mutation in the endogenous murine Matr3 locus. Heterozygous or homozygous MATR3 F115C knock-in mice were viable and did not exhibit motor deficits up to 2 years of age. The mutant mice showed no significant differences in the number of Purkinje cells or motor neurons compared to wild-type littermates. Neuropathological examination revealed an absence of MATR3 and TDP-43 pathology in Purkinje cells and motor neurons in the mutant mice. Together, our results suggest that the F115C mutation in MATR3 may not confer pathogenicity.
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Esclerose Lateral Amiotrófica/genética , Neurônios Motores/patologia , Proteínas Associadas à Matriz Nuclear/genética , Proteínas de Ligação a RNA/genética , Esclerose Lateral Amiotrófica/patologia , Animais , Técnicas de Introdução de Genes , Camundongos , Transtornos Motores/genética , Transtornos Motores/patologia , Neurônios Motores/metabolismo , Músculos/metabolismo , Músculos/patologia , Mutação PuntualRESUMO
BACKGROUND: Basal-like breast cancer (BLBC) or triple-negative breast cancer (TNBC) is an aggressive and highly metastatic subtype of human breast cancer. The present study aimed to elucidate the potential tumor-suppressive function of MATR3, an abundant nuclear protein, in BLBC/TNBC, whose cancer-relevance has not been characterized. METHODS: We analyzed in vitro tumorigenecity by cell proliferation and soft agar colony formation assays, apoptotic cell death by flow cytometry and Poly (ADP-ribose) polymerase (PARP) cleavage, epithelial-mesenchymal transition (EMT) by checking specific EMT markers with real-time quantitative PCR and in vitro migration and invasion by Boyden Chamber assays. To elucidate the underlying mechanism by which MATR3 functions as a tumor suppressor, we performed Tandem affinity purification followed by mass spectrometry (TAP-MS) and pathway analysis. We also scrutinized MATR3 expression levels in the different subtypes of human breast cancer and the correlation between MATR3 expression and patient survival by bioinformatic analyses of publicly available transcriptome datasets. RESULTS: MATR3 suppressed in vitro tumorigenecity, promoted apoptotic cell death and inhibited EMT, migration, and invasion in BLBC/TNBC cells. Various proteins regulating apoptosis were identified as MATR3-binding proteins, and YAP/TAZ pathway was suppressed by MATR3. MATR3 expression was inversely correlated with the aggressive and metastatic nature of breast cancer. Moreover, high expression levels of MATR3 were associated with a good prognosis of breast cancer patients. CONCLUSIONS: Our data demonstrate that MATR3 functions as a putative tumor suppressor in BLBC/TNBC cells. Also, MATR3 potentially plays a role as a biomarker in predicting chemotherapy-sensitivity and patient survival in breast cancer patients.
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Genes Supressores de Tumor , Proteínas Associadas à Matriz Nuclear/genética , Proteínas de Ligação a RNA/genética , Neoplasias de Mama Triplo Negativas , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias de Mama Triplo Negativas/genéticaRESUMO
The interaction of long noncoding RNAs (lncRNAs) with one or more RNA-binding proteins (RBPs) is important to a plethora of cellular and physiological processes. The lncRNA SNHG1 was reported to be aberrantly expressed and associated with poor patient prognosis in several cancers including neuroblastoma. However, the interacting RBPs and biological functions associated with SNHG1 in neuroblastoma remain unknown. In this study, we identified 283, 31, and 164 SNHG1-interacting proteins in SK-N-BE(2)C, SK-N-DZ, and SK-N-AS neuroblastoma cells, respectively, using a RNA-protein pull-down assay coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Twenty-four SNHG1-interacting RBPs were identified in common from these three neuroblastoma cell lines. RBPs MATR3, YBX1, and HNRNPL have the binding sites for SNHG1 predicted by DeepBind motif analysis. Furthermore, the direct binding of MATR3 with SNHG1 was validated by Western blot and confirmed by RNA immunoprecipitation assay (RIP). Coexpression analysis revealed that the expression of SNHG1 is positively correlated with MATR3 ( P = 3.402 × 10-13). The high expression of MATR3 is associated with poor event-free survival ( P = 0.00711) and overall survival ( P = 0.00064). Biological functions such as ribonucleoprotein complex biogenesis, RNA processing, and RNA splicing are significantly enriched and in common between SNHG1 and MATR3. In conclusion, we identified MATR3 as binding to SNHG1 and the interaction might be involved in splicing events that enhance neuroblastoma progression.
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Progressão da Doença , Neuroblastoma/patologia , Proteínas Associadas à Matriz Nuclear/metabolismo , Proteômica/métodos , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/metabolismo , Linhagem Celular Tumoral , Humanos , Neuroblastoma/mortalidade , Ligação Proteica , Splicing de RNA , Proteínas de Ligação a RNA/análise , Análise de SobrevidaRESUMO
The PDCD1 gene encodes PD-1, an important immune checkpoint protein and key immunotherapy target to treat cancer. PDCD1 is alternatively spliced to generate an exon 3-skipped isoform PD-1Δ3 that has been suggested to play an antagonistic role to PD-1, but the mechanism underlying alternative splicing of PDCD1 has never been explored. Here using a minigene system, we analysed the splicing pattern of PDCD1 in multiple cell lines and confirmed exon 3 skipping as the main alternative splicing event. Using deletion analysis of exon 3, we mapped two splicing enhancers in the exon: ESE3a and ESE3b. Using mutagenesis, RNA-affinity chromatography, mass spectrometry as well as depletion and overexpression of MATR3, we defined MATR3 as a splicing activator during PDCD1 exon 3 splicing that operates through binding to ESE3b. MATR3's splicing-stimulatory activity is counteracted by an RNA secondary structure around ESE3b and an RNA helicase DDX5. Furthermore, we identified ASOs that efficiently promotes PDCD1 exon 3 skipping in both minigene and endogenous-gene contexts. Our data support further study of the ASOs as potential drug candidates to treat cancer.
Assuntos
Processamento Alternativo , RNA Helicases DEAD-box/genética , Éxons , Proteínas Associadas à Matriz Nuclear/genética , Receptor de Morte Celular Programada 1/genética , Proteínas de Ligação a RNA/genética , Deleção de Sequência , Sequência de Bases , Linhagem Celular Tumoral , RNA Helicases DEAD-box/metabolismo , Elementos Facilitadores Genéticos , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Íntrons , Proteínas Associadas à Matriz Nuclear/metabolismo , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Ligação Proteica , Proteínas de Ligação a RNA/metabolismo , Alinhamento de SequênciaRESUMO
INTRODUCTION: Recently, mutations in the MATR3 gene were found to cause late-onset distal myopathy. The frequency and impact of respiratory involvement are not clear. METHODS: Respiratory parameters [maximum vital capacity (VCmax); forced expiratory volume (FEV1 ); peak expiratory flow (PEF), postural drop of VCmax from sitting to supine, maximum inspiratory muscle pressure (PImax), mouth occlusion pressure after 100 ms (P 0.1), peak cough flow, and blood-gas analysis] were monitored prospectively at baseline, and then 6 months and 12 months later in 8 patients with genetically confirmed MATR3 myopathy. RESULTS: All patients showed involvement of respiratory function. Six of 8 reported exertional dyspnea. At the end of follow-up, 5 of 8 had decreased VC, 7 of 8 had reduced PImax, and 5 of 7 had decreased partial pressure of oxygen (PO2 ). Within 12 months, respiratory parameters deteriorated non-significantly. No patient required non-invasive ventilation. CONCLUSIONS: There is a high risk of abnormal respiratory function with progressive worsening in MATR3 myopathy.
Assuntos
Miopatias Distais/complicações , Miopatias Distais/genética , Mutação/genética , Proteínas Associadas à Matriz Nuclear/genética , Proteínas de Ligação a RNA/genética , Transtornos Respiratórios/etiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The oncogenic role of Matrin-3 (MATR3), an a nuclear matrix protein, in HCC remains largely unknown. Here, we document the biological function of MATR3 in HCC based on integrated bioinformatics analysis and functional studies. According to the TCGA database, MATR3 expression was found to be positively correlated with clinicopathological characteristics in HCC. The receiver operating characteristic (ROC) curve and Kaplan-Meier (KM) curve displayed the diagnostic and prognostic potentials of MATR3 in HCC patients, respectively. Pathway enrichment analysis represented the enrichment of MATR3 in various molecular pathways, including the regulation of the cell cycle. Functional assays in HCC cell lines showed reduced proliferation of cells with stable silencing of MATR3. At the same time, the suppressive effects of MATR3 depletion on HCC development were verified by xenograft tumor experiments. Moreover, MATR3 repression also resulted in cell cycle arrest by modulating the expression of cell cycle-associated genes. In addition, the interaction of MATR3 with cell cycle-regulating factors in HCC cells was further corroborated with co-immunoprecipitation and mass spectrometry (Co-IP/MS). Furthermore, CIBERSORT and TIMER analyses showed an association between MATR3 and immune infiltration in HCC. In general, this study highlights the novel oncogenic function of MATR3 in HCC, which could comprehensively address how aberrant changes in the cell cycle promote HCC development. MATR3 might serve as a prognostic predictor and therapeutic target for HCC patients.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Ciclo Celular/genética , Divisão Celular , Biomarcadores , Proteínas de Ligação a RNA , Proteínas Associadas à Matriz Nuclear/genéticaRESUMO
Recent research has sparked a discussion on the spectrum of diseases linked to the MATR3 gene associated with amyotrophic lateral sclerosis and distal myopathy with vocal cord and pharyngeal weakness (VCPDM). To date, fewer than 50 cases of VCPDM have been reported in the literature. We aim to build upon the work of previous researchers by gathering additional information about VCPDM. In this study, we present six patients from four unrelated families affected by VCPDM. Our observations include patients exhibiting both the typical phenotype associated with MATR3-related distal myopathy and rare symptomatic manifestations of the disease. Notably, two cases presented with an asymmetric scapuloperoneal phenotype, leading in one case to an initial misdiagnosis of facioscapulohumeral muscular dystrophy.
RESUMO
Matrin-3 (MATR3) is an RNA-binding protein implicated in neurodegenerative and neurodevelopmental diseases. However, little is known regarding the role of MATR3 in cryptic splicing within the context of functional genes and how disease-associated variants impact this function. We show that loss of MATR3 leads to cryptic exon inclusion in many transcripts. We reveal that ALS-linked S85C pathogenic variant reduces MATR3 solubility but does not impair RNA binding. In parallel, we report a novel neurodevelopmental disease-associated M548T variant, located in the RRM2 domain, which reduces protein solubility and impairs RNA binding and cryptic splicing repression functions of MATR3. Altogether, our research identifies cryptic events within functional genes and demonstrates how disease-associated variants impact MATR3 cryptic splicing repression function.
Assuntos
Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/genética , Éxons/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , RNA , Proteínas Associadas à Matriz Nuclear/genéticaRESUMO
Matrin-3 (MATR3) was initially discovered as a component of the nuclear matrix about thirty years ago. Since then, accumulating studies have provided evidence that MATR3 not only plays a structural role in the nucleus, but that it is also an active protein involved in regulating gene expression at multiple levels, including chromatin organization, DNA transcription, RNA metabolism, and protein translation in the nucleus and cytoplasm. Furthermore, MATR3 may play a critical role in various cellular processes, including DNA damage response, cell proliferation, differentiation, and survival. In addition to the revelation of its biological role, recent studies have reported MATR3's involvement in the context of various diseases, including neurodegenerative and neurodevelopmental diseases, as well as cancer. Moreover, sequencing studies of patients revealed a handful of disease-associated mutations in MATR3 linked to amyotrophic lateral sclerosis (ALS), which further elevated the gene's importance as a topic of study. In this review, we synthesize the current knowledge regarding the diverse functions of MATR3 in DNA- and RNA-related processes, as well as its involvement in various diseases, with a particular emphasis on ALS.
Assuntos
Esclerose Lateral Amiotrófica , Regulação da Expressão Gênica , Proteínas Associadas à Matriz Nuclear , Matriz Nuclear , Humanos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Proteínas Associadas à Matriz Nuclear/metabolismo , Proteínas Associadas à Matriz Nuclear/genética , Matriz Nuclear/metabolismo , Animais , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genéticaRESUMO
Pterygium is a common eye surface disease with high recurrence and unclear pathogenesis. In current study, RNA sequencing was conducted in 6 pairs of human pterygium and conjunctival tissues, and Matr3 as a novel candidate gene was significantly reduced in pterygium compared to control tissues. Moreover, immunoprecipitation was performed to pull down MATR3, and WTAP specially interacting with MATR3 in control but not pterygium was identified by mass spectrum. Immunoprecipitation was performed to validate the interaction between MATR3 and WTAP/METTL3/METTL14 complex. (Methylated) RNA immunoprecipitation was performed to further reveal that the binding affinity of WTAP and MATR3 was lost at 3' UTR of RNA molecules of down-regulated genes in pterygium. Overall, we figured out the loss of intercrossing between MATR3 and N6-methyladenosine methyltransferase complex, as well as indicated the potential impact on transcription of target genes in pterygium.
Assuntos
Pterígio , Humanos , Metilação , Pterígio/genética , RNA , Túnica Conjuntiva/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Associadas à Matriz Nuclear/metabolismoRESUMO
Matrin 3 (MATR3) is one of the most abundant inner nuclear matrix proteins involved in multiple nuclear processes. However, to date, the biological role and prognostic relevance of MATR3 in human cancers still need to be explored. Therefore, the present study aimed to examine the expression levels and prognostic significance of MATR3 in clear cell renal cell carcinoma (ccRCC) patients. We assessed MATR3 immunohistochemical staining and RNA-seq data from publicly available data sets, and the results were analyzed with reference to clinicopathological characteristics and the overall survival of patients. Furthermore, the protein-protein interaction (PPI) network for MATR3 and its neighbors was constructed, functionally annotated, and screened for survival-related genes. MATR3 protein and mRNA levels were lower in tumor tissues compared to control tissues. Lower MATR3 protein (HR 2.36, 95%CI 1.41-3.97; p = 0.001) and mRNA (HR 2.01, 95%CI 1.46-2.75; p < 0.0001) expression levels were found to be a significant independent adverse prognostic factor for the patient's overall survival (OS). Moreover, of the candidate genes, the MRPL23 gene was identified as being the most predictive of OS, and combined MRPL23/MATR3 expression status predicted patient survival better than looking at each marker individually (HR 3.15, 95%CI 2.05-4.83; p < 0.0001). In conclusion, the results from the present investigation warrant further research into the biological and prognostic value of MATR3 and MRPL23 in ccRCC patients.
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The neuropathological hallmark of amyotrophic lateral sclerosis (ALS) is motor neuron degeneration in the spinal cord and cortex. Accumulating studies report that other neurons in the central nervous system (CNS) are also affected in ALS. Mutations in Matr3, which encodes a nuclear matrix protein involved in RNA splicing, have been linked to ALS. Previously, we generated a MATR3 S85C knock-in (KI) mouse model that recapitulates early-stage features of ALS. We reported that MATR3 S85C KI mice exhibit defects in lumbar spinal cord motor neurons and in cerebellar Purkinje cells, which are associated with reduced MATR3 immunoreactivity. Here, we show that neurons in various other regions of the CNS are affected in MATR3 S85C KI mice. Using histological analyses, we found selective loss of MATR3 staining in α-motor neurons, but not γ-motor neurons in the cervical and thoracic spinal cord. Loss of MATR3 was also found in parvalbumin-positive interneurons in the cervical, thoracic and lumbar spinal cord. In addition, we found the loss of MATR3 in subsets of upper motor neurons and hippocampal CA1 neurons. Collectively, our findings suggest that these additional neuronal types may contribute to the disease process in MATR3 S85C KI mice.
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PURPOSE: Matrin 3 (MATR3) is a nuclear matrix protein involved in mRNA stabilization, nuclear retention of hyper-edited RNAs, and RNA splicing. The role of MATR3 in cancer is still unclear. The present study aimed to investigate expression levels and prognostic significance of MATR3 in stage I and II non-small cell lung cancer (NSCLC) patients. METHODS: We examined MATR3 protein immunohistochemically in tumoral and non-tumoral tissue sections from n = 67 NSCLC patients treated at hospital, and MATR3 mRNA from The Cancer Genome Atlas (TCGA) cohort with respect to valid prognostic and predictive features, as well as treatment outcome. RESULTS: Significantly higher immunohistochemical levels of MATR3 protein were found in tumor-adjacent tissue compared to cancer (p = 0.049). A decrease in MATR3 protein expression was found to be a significant independent adverse prognostic factor for patients overall survival (p = 0.007). By contrast, we observed higher MATR3 mRNA levels in tumoral tissue compared to control lung tissues (p < 0.001). Based on the TCGA dataset, we reported that high MATR3 mRNA level was significantly associated with worse OS of NSCLC patients (p < 0.001); however, it was not an independent prognostic marker (p = 0.156). The discrepancies in prognostic significance of MATR3 gene mRNA and protein levels imply a need for further investigation. CONCLUSION: In conclusion, the present study warrants further investigation into the biological and prognostic value of MATR3 as a potential prognostic marker in early-stage NSCLC patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Prognóstico , Neoplasias Pulmonares/metabolismo , Proteínas Associadas à Matriz Nuclear/genética , Proteínas Associadas à Matriz Nuclear/metabolismo , RNA Mensageiro/genética , Proteínas de Ligação a RNARESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by prolonged fever, cytopenia, hepatosplenomegaly, and hemophagocytosis. This occurs as a result of activated macrophages and impaired function of natural killer cells and/or cytotoxic T lymphocytes. The NF-κB pathway plays a crucial role in hyperinflammation. Matrin3 (MATR3) is a nuclear RNA/DNA-binding protein that plays multiple roles in the regulation of gene expression. We enroll 62 patients diagnosed with secondary HLH and hemophagocytosis. Peripheral blood (PB) from 25 patients and 30 healthy volunteers and good quality bone marrow (BM) samples from 47 patients are collected and used for analysis. Clinical parameters, including age, sex, etiology, ferritin, fibrinogen, triglyceride, and viral infection status, had no association with survival prediction. Patients with downregulation of NF-κB and MATR3mRNA expression in the BM had a higher mortality rate. MATR3mRNA expression in PB was lower in patients compared to that in healthy volunteers. We use shRNA-MATR3-KD-THP1 cells to determine the efficacy of phagocytosis. We note that shRNA-MATR3-KD-THP1 cells had a higher phagocytic effect on necrotic Jurkat E6 cells and carboxylate modified polystyrene latex beads. Herein, we provide evidence of a new marker for clinical translation that can serve as a potential treatment target for secondary HLH.
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Mutations in the MATR3 gene are associated to distal myopathy with vocal cord and pharyngeal weakness (VCPDM), as well as familiar and sporadic motor neuron disease. To date, 12 VCPDM families from the United States, Germany, Japan, Bulgary, and France have been described in the literature. Here we report an Italian family with a propositus of a 40-year-old woman presenting progressive bilateral foot drop, rhinolalia, and distal muscular atrophy, without clinical signs of motor neuron affection. Her father, deceased some years before, presented a similar distal myopathy phenotype, while her 20-year-old son is asymptomatic. Myopathic changes with vacuolization were observed in muscle biopsy from the propositus. These results, together with the peculiar clinical picture, lead to MATR3 gene sequencing, which revealed a heterozygous p.S85C mutation in the propositus. The same mutation was found in her son. Over a 5-year follow-up, progression is mild in the propositus, while her son remains asymptomatic. Clinical, radiological, and pathological data of our propositus are presented and compared to previously reported cases of VCPDM. VCPDM turns out to be a quite homogenous phenotype of late-onset myopathy associated to p.S85C mutation in MATR3 gene. MATR3-related pathology, encompassing myopathy and motor neuron disease, represents an illustrative example of multisystem proteinopathy (MSP), such as other diseases associated to mutations in VCP, HNRNPA2B1, HNRNPA1, and SQSTM1 genes. The present report contributes to a further characterization of this still poorly understood pathology and points out the diagnostic utility of muscle biopsy in challenging cases.
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Mutations in the nuclear matrix protein Matrin 3 (MATR3) have been identified in amyotrophic lateral sclerosis and myopathy. To investigate the mechanisms underlying MATR3 mutations in neuromuscular diseases and efficiently screen for modifiers of MATR3 toxicity, we generated transgenic MATR3 flies. Our findings indicate that expression of wild-type or mutant MATR3 in motor neurons reduces climbing ability and lifespan of flies, while their expression in indirect flight muscles (IFM) results in abnormal wing positioning and muscle degeneration. In both motor neurons and IFM, mutant MATR3 expression results in more severe phenotypes than wild-type MATR3, demonstrating that the disease-linked mutations confer pathogenicity. We conducted a targeted candidate screen for modifiers of the MATR3 abnormal wing phenotype and identified multiple enhancers involved in axonal transport. Knockdown of these genes enhanced protein levels and insolubility of mutant MATR3. These results suggest that accumulation of mutant MATR3 contributes to toxicity and implicate axonal transport dysfunction in disease pathogenesis.