RESUMEN

Context: Liver function abnormalities have been reported in patients with Turner syndrome (TS); however, the pathophysiological mechanisms have not been well elucidated. Low-grade inflammation has been associated with metabolic dysfunction-associated steatotic liver disease. Objective: We studied systemic inflammatory indices [aspartate transaminase to lymphocyte ratio index (ALRI), aspartate transaminase to platelet ratio index (APRI), gamma-glutamyl transferase to platelet ratio (GPR), neutrophil-lymphocyte-ratio (NLR), and platelet lymphocyte ratio and examined their associations with the hepatic abnormalities observed in these subjects. Methods: We performed a retrospective analysis of the medical records of 79 patients with TS (mean age 32.5 ± 9.2 SD years) who were treated at the University Hospital of Nancy. Using matched-pair analyses based on age and body mass index (BMI), we compared 66 patients with TS (25.6 ± 7.3 years; BMI 25.9 ± 6.3 kg/m2) to 66 healthy control participants (24.7 ± 6.8 years; BMI 26 ± 6.7 kg/m2). Results: Liver function abnormalities were present in 57% of the patients with TS. The ALRI, APRI, GPR, and NLR were significantly greater in patients with TS who presented with liver dysfunction than in patients with TS who had normal liver function. According to the matched-pair analyses, the ALRI, APRI, and GPR were greater in patients with TS than in healthy control participants. Logistic regression revealed that a diagnosis of TS was significantly associated with ALRI, APRI, and GPR and liver dysfunction. Conclusion: Noninvasive inflammatory indices (ALRI, APRI, and GPR) might be a promising indicators of liver dysfunction in patients with TS. Future prospective studies are needed to confirm our findings and to explore the clinical significance and prognostic value of systemic inflammatory indices in Turner syndrome.

RESUMEN

HuR regulates cytoplasmic mRNA stability and translatability, with its expression correlating with adverse outcomes in various cancers. This study aimed to assess the prognostic value and pro-oncogenic properties of HuR and its post-translational isoforms methyl-HuR and phospho-HuR in endometrial adenocarcinoma. Examining 89 endometrioid adenocarcinomas, we analyzed the relationship between HuR nuclear or cytoplasmic immunostaining, tumor-cell proliferation, and patient survival. HuR cytoplasmic expression was significantly increased in grade 3 vs. grade 1 adenocarcinomas (p < 0.001), correlating with worse overall survival (OS) (p = 0.02). Methyl-HuR cytoplasmic expression significantly decreased in grade 3 vs. grade 1 adenocarcinomas (p < 0.001) and correlated with better OS (p = 0.002). Phospho-HuR nuclear expression significantly decreased in grade 3 vs. grade 1 adenocarcinomas (p < 0.001) and non-significantly correlated with increased OS (p = 0.06). Cytoplasmic HuR expression strongly correlated with proliferation markers MCM6 (rho = 0.59 and p < 0.001) and Ki67 (rho = 0.49 and p < 0.001). Conversely, these latter inversely correlated with cytoplasmic methyl-HuR and nuclear phospho-HuR. Cytoplasmic HuR expression is a poor prognosis marker in endometrioid endometrial adenocarcinoma, while cytoplasmic methyl-HuR and nuclear phosphoHuR expressions are markers of better prognosis. This study highlights HuR as a promising potential therapeutic target, especially in treatment-resistant tumors, though further research is needed to understand the mechanisms regulating HuR subcellular localization and post-translational modifications.

Asunto(s)

Carcinoma Endometrioide , Proteína 1 Similar a ELAV , Neoplasias Endometriales , Femenino , Humanos , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Proliferación Celular , Citoplasma , Citosol , Neoplasias Endometriales/genética , Neoplasias Endometriales/metabolismo , Proteína 1 Similar a ELAV/genética , Proteína 1 Similar a ELAV/metabolismo

RESUMEN

Introduction: Meningiomas are the most common type of primary central nervous system tumors. In about 80% cases, these tumors are benign and grow very slowly, but the remainder 20% can unlock higher proliferation rates and become malignant. In this study we examined two miRs, miR-16 and miR-519, and evaluated their role in tumorigenesis and cell growth in human meningioma. Methods: A cohort of 60 intracranial grade 1 and grade 2 human meningioma plus 20 healthy meningeal tissues was used to quantify miR-16 and miR-519 expressions. Cell growth and dose-response assays were performed in two human meningioma cell lines, Ben-Men-1 (benign) and IOMM-Lee (aggressive). Transcriptomes of IOMM-lee cells were measured after both miR-mimics transfection, followed by integrative bioinformatics to expand on available data. Results: In tumoral tissues, we detected decreased levels of miR-16 and miR-519 when compared with arachnoid cells of healthy patients (miR-16: P=8.7e-04; miR-519: P=3.5e-07). When individually overexpressing these miRs in Ben-Men-1 and IOMM-Lee, we observed that each showed reduced growth (P<0.001). In IOMM-Lee cell transcriptomes, downregulated genes, among which ELAVL1/HuR (miR-16: P=6.1e-06; miR-519:P=9.38e-03), were linked to biological processes such as mitotic cell cycle regulation, pre-replicative complex, and brain development (FDR<1e-05). Additionally, we uncovered a specific transcriptomic signature of miR-16/miR-519-dysregulated genes which was highly enriched in HuR targets (>6-fold; 79.6% of target genes). Discussion: These results were confirmed on several public transcriptomic and microRNA datasets of human meningiomas, hinting that the putative tumor suppressor effect of these miRs is mediated, at least in part, via HuR direct or indirect inhibition.

RESUMEN

The aim of this study was to evaluate the prognostic value of MCM6, in comparison with Ki-67, in two series of grade 1 and 2 meningiomas, and to evaluate its correlation with methylation classes. The first cohort included 100 benign (grade 1, World Health Organization 2021) meningiomas, and the second 69 atypical meningiomas (grade 2). Immunohistochemical Ki-67 and MCM6 labeling indices (LI) were evaluated independently by two observers. Among the atypical meningiomas, 33 cases were also studied by genome-wide DNA methylation. In grade 2 meningiomas, but not grade 1, both Ki-67 and MCM6 LIs were correlated with PFS (p = 0.004 and p = 0.005, respectively; Cox univariate analyses). Additionally, MCM6 was correlated with overall survival only in univariate analysis. In a multivariate model, including mitotic index, Ki-67, MCM6, age, sex, and the quality of surgical resection, only MCM6 was correlated with PFS (p = 0.046). Additionally, we found a significant correlation between PTEN loss and high MCM6 or Ki-67 LIs. Although no correlation was found with the methylation classes and subtypes returned by the meningioma algorithm MNGv2.4., MCM6 LI was significantly correlated with the methylation of 2 MCM6 gene body loci. In conclusion, MCM6 is a relevant prognostic marker in atypical meningiomas. This reproducible and easy-to-use marker allows the identification of a highly aggressive subtype of proliferative meningiomas, characterized notably by frequent PTEN losses, which was previously reported to be sensitive to histone deacetylase inhibitors.

RESUMEN

Meningiomas are the most common primary tumors of the central nervous system. Based on the 2021 WHO classification, they are classified into three grades reflecting recurrence risk and aggressiveness. However, the WHO's histopathological criteria defining these grades are somewhat subjective. Together with reliable immunohistochemical proliferation indices, other molecular markers such as those studied with genome-wide epigenetics promise to revamp the current prognostic classification. In this study, 48 meningiomas of various grades were randomly included and explored for DNA methylation with the Infinium MethylationEPIC microarray over 850k CpG sites. We conducted differential and correlative analyses on grade and several proliferation indices and markers, such as mitotic index and Ki-67 or MCM6 immunohistochemistry. We also set up Cox proportional hazard models for extensive associations between CpG methylation and survival. We identified loci highly correlated with cell growth and a targeted methylation signature of regulatory regions persistently associated with proliferation, grade, and survival. Candidate genes under the control of these regions include SMC4, ESRRG, PAX6, DOK7, VAV2, OTX1, and PCDHA-PCDHB-PCDHG, i.e., the protocadherin gene clusters. This study highlights the crucial role played by epigenetic mechanisms in shaping dysregulated cellular proliferation and provides potential biomarkers bearing prognostic and therapeutic value for the clinical management of meningioma.

RESUMEN

Previously, the in vitro growth of cancer stem cells in the form of tumor spheres from five different brain cancer cell lines was found to be methionine-dependent. As this earlier work indicated that ALDH1L2, a folate-dependent mitochondria aldehyde dehydrogenase gene, is upregulated in glioblastoma stem cells, we invalidated this gene using CRISPR-cas 9 technique in this present work. We reported here that this invalidation was effective in U251 glioblastoma cells, and no cas9 off target site could be detected by genome sequencing of the two independent knockout targeting either exon I or exon III. The knockout of ALDH1L2 gene in U251 cells rendered the growth of the cancer stem cells of U251 methionine independent. In addition, a much higher ROS (reactive oxygen radicals) level can be detected in the knockout cells compared to the wild type cells. Our evidence here linked the excessive ROS level of the knockout cells to reduced total cellular NADPH. Our evidence suggested also that the cause of the slower growth of the knockout turmor sphere may be related to its partial differentiation.

Asunto(s)

Glioblastoma , Línea Celular Tumoral , Glioblastoma/metabolismo , Humanos , Metionina/metabolismo , Células Madre Neoplásicas/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) has emerged globally and is associated with inflammatory signaling. The underlying mechanisms remain poorly delineated, although NAFLD has attracted considerable attention and been extensively investigated. Recent publications have determined that angiotensin II (Ang II) plays an important role in stimulating NAFLD progression by causing lipid metabolism disorder and insulin resistance through its main receptor, Ang II type 1 receptor (AT1R). Herein, we explored the effect of supplementary S-adenosylmethionine (SAM), which is the main biological methyl donor in mammalian cells, in regulating AT1R-associated protein (ATRAP), which is the negative regulator of AT1R. We found that SAM was depleted in NAFLD and that SAM supplementation ameliorated steatosis. In addition, in both high-fat diet-fed C57BL/6 rats and L02 cells treated with oleic acid (OA), ATRAP expression was downregulated at lower SAM concentrations. Mechanistically, we found that the subcellular localization of human antigen R (HuR) was determined by the SAM concentration due to protein methylation modification. Moreover, HuR was demonstrated to directly bind ATRAP mRNA and control its nucleocytoplasmic shuttling. Thus, SAM was suggested to upregulate ATRAP protein expression by maintaining the export of its mRNA from the nucleus. Taken together, our findings suggest that SAM can positively regulate ATRAP in NAFLD and may have various potential benefits for the treatment of NAFLD.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteína 1 Similar a ELAV/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , S-Adenosilmetionina/metabolismo , Animales , Dieta Alta en Grasa , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Receptor de Angiotensina Tipo 1/genética , Transfección , Regulación hacia Arriba

RESUMEN

Methionine-dependency is a common feature of cancer cells, which cannot proliferate without constant inputs of exogenous methionine even in the presence of its precursor, homocysteine. The endogenous synthesis of methionine is catalyzed by methionine synthase, which transfers the methyl group of 5-methyltetrahydrofolate (5-methylTHF) to homocysteine in the presence of vitamin B12 (cobalamin, cbl). Diverse mechanisms can produce it, including somatic mutations, aberrant DNA methylation (epimutations) and altered expression of genes. Around twenty somatic mutations have been reported as a cause of methionine dependency. Some of them are contributors but not sufficient on their own to cause methionine dependency. Epigenetic invalidation of MMACHC gene expression triggers methionine dependency of the MeWo-LC1 melanoma cancer cell line. This epimutation is generated by aberrant antisense transcription of the adjacent gene PRDX1. Methionine dependency involves the abnormal expression of 1-CM genes in cancer stem cells. It is related to an increased demand for methionine and SAM, which is not compensated by the increased production of formate by glycine decarboxylase pathway in lung cancer tumor spheres. Tumor spheres of glioblastoma U251 are methionine-dependent through disruption of folate metabolism. The rescue of the growth of glioblastoma stem cells by folate shows the considerable importance to evaluate the influence of supplements and dietary intake of folate on the risk of tumor development, in particular in countries subjected to mandatory food fortification in folic acid. Dietary methionine restriction or the use of methioninase represent promising anticancer therapeutic strategies that deserve to be explored in combination with chemotherapy.

Asunto(s)

Ácido Fólico/metabolismo , Homocisteína/metabolismo , Metionina/metabolismo , Neoplasias/metabolismo , Células Madre Neoplásicas/metabolismo , Vitamina B 12/metabolismo , Línea Celular Tumoral , Epigénesis Genética , Humanos , Neoplasias/patología , Células Madre Neoplásicas/patología

RESUMEN

The identification of viability-associated long noncoding RNAs (lncRNAs) is a means of uncovering therapeutic approaches for hepatocellular carcinoma (HCC). In addition, aberrant genome-wide hypomethylation has been implicated in HCC initiation and progression. However, the relationship between lncRNA dysregulation and genome-wide hypomethylation in hepatocarcinogenesis has not been fully elucidated. A novel lncRNA named LINC00662 was previously demonstrated to play a role in gastrointestinal cancer. In this study, we demonstrated that this lncRNA was correlated with survival and exhibited oncogenic properties, both in vitro and in vivo. Moreover, we determined that LINC00662 could lead to genome-wide hypomethylation and alter the genomic methylation profile by synchronously reducing the S-adenosylmethionine (SAM) level and enhancing the S-adenosylhomocysteine (SAH) level. Mechanistically, LINC00662 was determined to regulate the key enzymes influencing SAM and SAH levels, namely, methionine adenosyltransferase 1A (MAT1A) and S-adenosylhomocysteine hydrolase (AHCY), by RNA-RNA and RNA-protein interactions. In addition, we demonstrated that some SAM-dependent HCC-promoting genes could be regulated by LINC00662 by altering the methylation status of their promoters via the LINC00662-coupled axes of MAT1A/SAM and AHCY/SAH. Taken together, the results of this this study indicate that LINC00662 could be a potential biomarker for HCC therapy. More importantly, we proposed a new role of lncRNA in regulating genomic methylation to promote oncogene activation.

Asunto(s)

Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Metilación de ADN/genética , Progresión de la Enfermedad , Genoma Humano , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , ARN Largo no Codificante/metabolismo , Regiones no Traducidas 3'/genética , 5-Metilcitosina/metabolismo , Adenosilhomocisteinasa/metabolismo , Adulto , Carcinogénesis/genética , Carcinogénesis/patología , Línea Celular Tumoral , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Metionina Adenosiltransferasa/metabolismo , Proteolisis , ARN Largo no Codificante/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , S-Adenosilhomocisteína/metabolismo , S-Adenosilmetionina/metabolismo , Análisis de Supervivencia , Ubiquitina/metabolismo , Regulación hacia Arriba/genética

RESUMEN

Anaplastic oligodendroglioma (AO), IDH-mutant and 1p/19q codeleted (IDHmut+/1p19qcodel), is a high-grade glioma with only limited prognostic markers. The primary objective of this study was to evaluate, by immunohistochemistry, the prognostic value of two proliferation markers, MCM6 and Ki-67, in a large series of IDHmut+/1p19qcodel AO included in the POLA ("Prise en charge des Oligodendrogliomes Anaplasiques") French national multicenter network. We additionally examined the transcriptome obtained from this series to understand the functional pathways dysregulated with the mRNA overexpression of these two markers. The labeling indices (LI) of MCM6 and Ki-67 were obtained via computer-assisted color image analyses on immunostained AO tissues of the cohort (n = 220). Furthermore, a subgroup of AO (n = 68/220) was used to perform transcriptomic analyses. A high LI of either MCM6 (≥50%) or Ki-67 (≥15%) correlated with shorter overall survival, both in univariate (P = 0.013 and P = 0.004, respectively) and multivariate analyses (P = 0.027; multivariate Cox model including age, mitotic index, MCM6 and Ki-67). MCM6 and Ki-67 LI also correlated with overall survival in an additional retrospective cohort of 30 grade II IDHmut+/1p19qcodel oligodendrogliomas. The prognostic value of MCM6 mRNA level was confirmed in The Cancer Genome Atlas (TCGA) IDHmut+/1p19qcodel gliomas. The transcriptomic approach revealed that high transcriptional expressions of MCM6 and MKI67 were both linked positively with cell cycle progression, DNA replication, mitosis, pro-neural phenotype as well as neurogenesis, and negatively with microglial cell activation, immune response, positive regulation of myelination, oligodendrocyte development, beta-amyloid binding and postsynaptic specialization. In conclusion, the overexpression of MCM6 and/or Ki-67 is independently associated to shorter overall survival in IDHmut+/1p19qcodel AO. These two easy-to-use and cost-effective markers could thus be used concurrently in routine pathology practice. Additionally, the transcriptomic analyses showed that AO with high proliferation index have down-regulated immune response and lower microglial cells activation, and bears pro-neural phenotype.

Asunto(s)

Neoplasias Encefálicas/metabolismo , Eliminación de Gen , Isocitrato Deshidrogenasa/genética , Antígeno Ki-67/metabolismo , Componente 6 del Complejo de Mantenimiento de Minicromosoma/metabolismo , Mutación , Oligodendroglioma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Femenino , Francia , Perfilación de la Expresión Génica , Humanos , Isocitrato Deshidrogenasa/metabolismo , Masculino , Persona de Mediana Edad , Índice Mitótico , Oligodendroglioma/genética , Oligodendroglioma/mortalidad , Oligodendroglioma/patología , Pronóstico , Tasa de Supervivencia , Adulto Joven

RESUMEN

BACKGROUND: The molecular consequences of inborn errors of vitamin B12 or cobalamin metabolism are far from being understood. Moreover, innovative therapeutic strategies are needed for the treatment of neurological outcomes that are usually resistant to conventional treatments. Our previous findings suggest a link between SIRT1, cellular stress and RNA binding proteins (RBP) mislocalization in the pathological mechanisms triggered by impaired vitamin B12 metabolism. OBJECTIVES AND METHODS: The goal of this study was to investigate the effects of the pharmacological activation of SIRT1 using SRT1720 on the molecular mechanisms triggered by impaired methionine synthase activity. Experiments were performed in vitro with fibroblasts from patients with the cblG and cblC inherited defects of vitamin B12 metabolism and in vivo with an original transgenic mouse model of methionine synthase deficiency specific to neuronal cells. Subcellular localization of the RBPs HuR, HnRNPA1, RBM10, SRSF1 and Y14 was investigated by immunostaining and confocal microscopy in patient fibroblasts. RBPs methylation and phosphorylation were studied by co-immunoprecipitation and proximity ligation assay. Cognitive performance of the transgenic mice treated with SRT1720 was measured with an aquatic maze. RESULTS: Patient fibroblasts with cblC and cblG defects of vitamin B12 metabolism presented with endoplasmic reticulum stress, altered methylation, phosphorylation and subcellular localization of HuR, HnRNPA1 and RBM10, global mRNA mislocalization and increased HnRNPA1-dependent skipping of IRF3 exons. Incubation of fibroblasts with cobalamin, S-adenosyl methionine and okadaic acid rescued the localization of the RBPs and mRNA. The SIRT1 activating compound SRT1720 inhibited ER stress and rescued RBP and mRNA mislocalization and IRF3 splicing. Treatment with this SIRT1 agonist prevented all these hallmarks in patient fibroblasts but it also improved the deficient hippocampo-dependent learning ability of methionine synthase conditional knock-out mice. CONCLUSIONS: By unraveling the molecular mechanisms triggered by inborn errors of cbl metabolism associating ER stress, RBP mislocalization and mRNA trafficking, our study opens novel therapeutic perspectives for the treatment of inborn errors of vitamin B12 metabolism.

Asunto(s)

Disfunción Cognitiva/tratamiento farmacológico , Proteínas de Unión al ARN/metabolismo , Sirtuina 1/farmacología , Deficiencia de Vitamina B 12/complicaciones , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/deficiencia , Animales , Células Cultivadas , Disfunción Cognitiva/etiología , Estrés del Retículo Endoplásmico , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Errores Innatos del Metabolismo/complicaciones , Ratones , Ratones Noqueados , ARN Mensajero/metabolismo , Sirtuina 1/metabolismo , Sirtuina 1/uso terapéutico , Vitamina B 12/genética

RESUMEN

Methionine dependency of tumor growth, although not well-understood, is detectable by 11C-methionine positron emission tomography and may contribute to the aggressivity of glioblastomas (GBM) and meningiomas. Cytosolic folate cycle is required for methionine synthesis. Its dysregulation may influence cell reprogramming towards pluripotency. We evaluated methionine-dependent growth of monolayer (ML) cells and stem cell-like tumor spheres (TS) derived from 4 GBM (U251, U87, LN299, T98G) and 1 meningioma (IOMM-LEE) cell lines. Our data showed that for all cell lines studied, exogenous methionine is required for TS formation but not for ML cells proliferation. Furthermore, for GBM cell lines, regardless of the addition of folate cycle substrates (folic acid and formate), the level of 3 folate isoforms, 5-methytetrahydrofolate, 5,10-methenyltetrahydrofolate, and 10-formyltetrahydrofolate, were all downregulated in TS relative to ML cells. Unlike GBM cell lines, in IOMM-LEE cells, 5-methyltetrahydrofolate was actually more elevated in TS than ML, and only 5,10-methenyltetrahydrofolate and 10-formyltetrahydrofolate were downregulated. The functional significance of this variation in folate cycle repression was revealed by the finding that Folic Acid and 5-methyltetrahydrofolate promote the growth of U251 TS but not IOMM-LEE TS. Transcriptome-wide sequencing of U251 cells revealed that DHFR, SHMT1, and MTHFD1 were downregulated in TS vs ML, in concordance with the low activity cytosolic folate cycle observed in U251 TS. In conclusion, we found that a repressed cytosolic folate cycle underlies the methionine dependency of GBM and meningioma cell lines and that 5-methyltetrahydrofolate is a key metabolic switch for glioblastoma TS formation. The finding that folic acid facilitates TS formation, although requiring further validation in diseased human tissues, incites to investigate whether excessive folate intake could promote cancer stem cells formation in GBM patients.

Asunto(s)

Reprogramación Celular/genética , Ácido Fólico/metabolismo , Glioblastoma/genética , Meningioma/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Reprogramación Celular/efectos de los fármacos , Citosol/metabolismo , Metilación de ADN/genética , Ácido Fólico/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Meningioma/metabolismo , Meningioma/patología , Metionina/farmacología , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Antígenos de Histocompatibilidad Menor/genética , Células Madre Neoplásicas/metabolismo , Células Madre Pluripotentes/metabolismo , Tetrahidrofolato Deshidrogenasa/genética , Tetrahidrofolatos/genética

RESUMEN

Current histoprognostic parameters and prognostic scores used in paragangliomas and pheochromocytomas do not adequately predict the risk of metastastic progression and survival. Here, using a series of 147 cases of paraganglioma and pheochromocytoma, we designed and evaluated the potential of a new score, the COPPS (COmposite Pheochromocytoma/paraganglioma Prognostic Score), by taking into consideration three clinico-pathological features (including tumor size, necrosis, and vascular invasion), and the losses of PS100 and SDHB immunostain to predict the risk of metastasis. We compared also the performance of the COPPS with several presently used histoprognostic parameters in risk assessment of these tumors. A PASS score (Pheochromocytoma of the Adrenal gland Scaled Score) ≥ 6 was significantly associated with the occurrence of metastases (P < 0.0001) and shorter PFS (P = 0.013). In addition, both MCM6 and Ki-67 LI correlated with worse PFS (P = 0.004 and P < 0.0001, respectively), and MCM6, but not Ki-67, was significantly higher in metastatic group (P = 0.0004). Loss of PS100 staining correlated with the occurrence of metastasis (P < 0.0001) and shorter PFS (P < 0.0001). At a value of greater or equal to 3, the COPPS correlated with shorter PFS (P < 0.0001), and predicted reproducibly (weighted Kappa coefficient, 0.863) the occurrence of metastases with a sensitivity of 100.0% and specificity of 94.7%. It thus surpassed those found for either PASS, SDHB, MCM6, or Ki-67 alone. In conclusion, while validation is still necessary in independent confirmatory cohorts, COPPS could be of great potential for the risk assessment of metastasis and progression in paragangliomas and pheochromocytomas.

Asunto(s)

Metástasis de la Neoplasia/diagnóstico , Paraganglioma/mortalidad , Feocromocitoma/mortalidad , Feocromocitoma/patología , Adolescente , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Procesos Neoplásicos , Pronóstico , Supervivencia sin Progresión , Medición de Riesgo , Adulto Joven

RESUMEN

The molecular mechanisms that underlie the neurological manifestations of patients with inherited diseases of vitamin B12 (cobalamin) metabolism remain to date obscure. We observed transcriptomic changes of genes involved in RNA metabolism and endoplasmic reticulum stress in a neuronal cell model with impaired cobalamin metabolism. These changes were related to the subcellular mislocalization of several RNA binding proteins, including the ELAVL1/HuR protein implicated in neuronal stress, in this cell model and in patient fibroblasts with inborn errors of cobalamin metabolism and Cd320 knockout mice. The decreased interaction of ELAVL1/HuR with the CRM1/exportin protein of the nuclear pore complex and its subsequent mislocalization resulted from hypomethylation at R-217 produced by decreased S-adenosylmethionine and protein methyl transferase CARM1 and dephosphorylation at S221 by increased protein phosphatase PP2A. The mislocalization of ELAVL1/HuR triggered the decreased expression of SIRT1 deacetylase and genes involved in brain development, neuroplasticity, myelin formation, and brain aging. The mislocalization was reversible upon treatment with siPpp2ca, cobalamin, S-adenosylmethionine, or PP2A inhibitor okadaic acid. In conclusion, our data highlight the key role of the disruption of ELAVL1/HuR nuclear export, with genomic changes consistent with the effects of inborn errors of Cbl metabolisms on brain development, neuroplasticity and myelin formation.

Asunto(s)

Transporte Biológico/genética , Proteína 1 Similar a ELAV/metabolismo , Carioferinas/metabolismo , Enfermedades Metabólicas/genética , Proteínas de Unión al ARN/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Vitamina B 12/metabolismo , Animales , Encéfalo/patología , Proteínas Adaptadoras de Señalización CARD/metabolismo , Línea Celular Tumoral , Núcleo Celular/metabolismo , Estrés del Retículo Endoplásmico/genética , Humanos , Metilación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ácido Ocadaico/farmacología , Fosforilación , Proteína Fosfatasa 2/antagonistas & inhibidores , Proteína Fosfatasa 2/farmacología , ARN Mensajero/metabolismo , S-Adenosilmetionina/farmacología , Sirtuina 1/biosíntesis , Proteína Exportina 1

RESUMEN

Metabolic disorders have become among the most serious threats to human health, leading to severe chronic diseases such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease, as well as cardiovascular diseases. Interestingly, despite the fact that each of these diseases has different physiological and clinical symptoms, they appear to share certain pathological traits such as intracellular stress and inflammation induced by metabolic disturbance stemmed from over nutrition frequently aggravated by a modern, sedentary life style. These modern ways of living inundate cells and organs with saturating levels of sugar and fat, leading to glycotoxicity and lipotoxicity that induce intracellular stress signaling ranging from oxidative to ER stress response to cope with the metabolic insults (Mukherjee, et al., 2015). In this review, we discuss the roles played by cellular stress and its responses in shaping metabolic disorders. We have summarized here current mechanistic insights explaining the pathogenesis of these disorders. These are followed by a discussion of the latest therapies targeting the stress response pathways.

RESUMEN

Minichromosome maintenance complex component 6 (MCM6) is involved in initiating DNA replication and is upregulated during licensed G0 phase of the cell cycle. This early expression permits its labeling of more proliferating cells than those by Ki-67. Here using a cohort of 89 endometrioid adenocarcinoma, we report findings made on the prognostic value of MCM6 based on immunohistochemical labeling index (LI) of the protein in comparison with that of Ki67 as no such information is currently available. Additionally, we examined the prognostic values of these markers based on their mRNA expression using a cohort of uterine corpus endometrial carcinoma (UCEC, n = 307) taken from The Cancer Genome Atlas (TCGA) database. Our evidence indicated the presence of a positive correlation between the LI of MCM6 and the histological grade of endometrioid endometrial adenocarcinoma (grade I, 66.7%; grade II, 75.3%; grade III, 81.4%; p < 0.001) and an inverse correlation between the LI of MCM6 and the overall and progression-free survival (p = 0.02 for both). The LI of Ki-67 correlated with grade (p < 0.001), but not survival. The MCM6 and Ki-67 inter-observer intra-class correlation coefficients were excellent: 0.84 (95% confidence interval, 0.83-0.91) and 0.84 (0.77-0.90), respectively. For in silico analyses of the TCGA cohort, both univariate and multivariate Cox analyses (p = 0.003 and p = 0.03, respectively) revealed high MCM6 mRNA Z-scores associated with reduced overall survival. This association was absent for Ki-67. MCM6 is thus a highly reproducible marker of poor prognosis in endometrial cancer. Evaluation of MCM6 should thus be considered in daily practice for risk stratification.

Asunto(s)

Biomarcadores de Tumor/análisis , Carcinoma Endometrioide/patología , Componente 6 del Complejo de Mantenimiento de Minicromosoma/biosíntesis , Anciano , Carcinoma Endometrioide/mortalidad , Estudios de Cohortes , Supervivencia sin Enfermedad , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/patología , Femenino , Humanos , Persona de Mediana Edad , Componente 6 del Complejo de Mantenimiento de Minicromosoma/análisis , Pronóstico , Estudios Retrospectivos

RESUMEN

Important progress has been made on cytokine signaling in response to kidney injury in the past decade, especially cytokine signaling mediated by extracellular vesicles (EVs). For example, EVs released by injured renal tubular epithelial cells (TECs) can regulate intercellular communications and influence tissue recovery via both regulating the expression and transferring cytokines, growth factors, as well as other bioactive molecules at the site of injury. The effects of EVs on kidney tissue seem to vary depending on the sources of EVs; however, the literature data are often inconsistent. For example, in rodents EVs derived from mesenchymal stem cells (MSC-EVs) and endothelial progenitor cells (EPC-EVs) can have both beneficial and harmful effects on injured renal tissue. Caution is thus needed in the interpretation of these data as contradictory findings on EVs may not only be related to the origin of EVs, they can also be caused by the different methods used for EV isolation and the physiological and pathological states of the tissues/cells under which they were obtained. Here, we review and discuss our current understanding related to the immunomodulatory function of EVs in renal tubular repair in the hope of encouraging further investigations on mechanisms related to their antiinflammatory and reparative role to better define the therapeutic potential of EVs in renal diseases.

Asunto(s)

Lesión Renal Aguda/metabolismo , Vesículas Extracelulares/metabolismo , Glomérulos Renales/metabolismo , Túbulos Renales/metabolismo , Células Madre Mesenquimatosas/metabolismo , Animales , Humanos , Recuperación de la Función/fisiología

RESUMEN

Mechanisms that control mammalian gene expression, notably mRNA stability and translation, have major functions in the modulation of the cellular response to internal and external stimuli. Altered posttranscriptional regulation of gene expression has been associated with many diseases. Such types of deregulation have also recently been noted on the inflammatory cytokines pertinent to kidney inflammation. In this article, we summarize briefly the recent knowledge obtained from both human and experimental systems on the details of posttranscriptional regulation of gene expression related to the control of mRNA stability and discuss their relevance in regulating cytokine expression linked to the inflammatory processes in kidney. Despite the fact that not many such examples in human kidney diseases have been uncovered with great mechanistic details, studies in experimental models suggest that the mRNA stability control is more than meets the eye. Therapeutic potentials aiming at regulating cytokine expression via posttranscriptional modification of mRNA half-life are thus discussed.

Asunto(s)

Citocinas/genética , Regulación de la Expresión Génica/genética , Nefritis/metabolismo , Procesamiento Postranscripcional del ARN , Estabilidad del ARN , ARN Mensajero/metabolismo , Ciclooxigenasa 2/metabolismo , Citocinas/biosíntesis , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Complejo Multienzimático de Ribonucleasas del Exosoma , Humanos , Túbulos Renales Proximales/metabolismo , Nefritis/genética , ARN Mensajero/genética , Proteínas de Unión al ARN/metabolismo , Secuencias Reguladoras de Ácidos Nucleicos , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismo , Transactivadores/metabolismo

RESUMEN

Monoclonal gammopathies (MG) are classically associated with lytic bone lesions, hypercalcemia, anemia, and renal insufficiency. However, in some cases, symptoms of endocrine dysfunction are more prominent than these classical signs and misdiagnosis can thus be possible. This concerns especially the situation where the presence of M-protein is limited and the serum protein electrophoresis (sPEP) appears normal. To understand the origin of the endocrine symptoms associated with MG, we overview here the current knowledge on the complexity of interactions between cytokines and the endocrine system in MG and discuss the perspectives for both the diagnosis and treatments for this class of diseases. We also illustrate the role of major cytokines and growth factors such as IL-6, IL-1ß, TNF-α, and VEGF in the endocrine system, as these tumor-relevant signaling molecules not only help the clonal expansion and invasion of the tumor cells but also influence cellular metabolism through autocrine, paracrine, and endocrine mechanisms. We further discuss the broader impact of these tumor environment-derived molecules and proinflammatory state on systemic hormone signaling. The diagnostic challenges and clinical work-up are illustrated from the point of view of an endocrinologist.

Asunto(s)

Citocinas/metabolismo , Sistema Endocrino/metabolismo , Sistema Endocrino/patología , Células Plasmáticas/metabolismo , Células Plasmáticas/patología , Animales , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Neoplasias de Células Plasmáticas , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo

RESUMEN

HuR regulates cytoplasmic mRNA stability and translatability, and the HuR expression level has been shown to correlate with poor disease outcome in several cancer types; however, the prognostic value and potential pro-oncogenic properties of HuR in meningioma remain unclear. Thus, in the present study, we analysed 85 meningioma tissue samples to establish the relationship between HuR expression, tumour cell proliferation, and/or patient survival. In addition, we examined the anti-proliferative effects of HuR knockdown in two meningioma cell lines (IOMM-Lee and Ben-Men-1) and conducted transcriptome-wide analyses (IOMM-Lee cells) to elucidate the molecular consequences of HuR knockdown. The results of the present study showed HuR cytoplasmic expression to correlate positively with tumour grade (p = 1.2 × 10-8 ) and negatively with progression-free and overall survival (p = 0.01) time in human meningioma tissues. In vitro, siHuR-induced HuR knockdown was shown to reduce the growth of both Ben-Men-1 (p = 2 × 10-8 ) and IOMM-Lee (p = 4 × 10-9 ) cells. Transcriptome analyses revealed HuR knockdown in IOMM-Lee cells to deregulate the HIF1A signalling pathway (p = 1.5 × 10-6 ) and to up-regulate the expression of genes essential for the assembly of the cytoplasmic mRNA processing body, global genome nucleotide-excision repair, poly(A)-specific ribonuclease activity, the positive regulation of apoptosis and of cell cycle arrest, and the negative regulation of RNA splicing [p(FDR) < 0.001]. Interestingly, HuR knockdown under hypoxic culture conditions further potentiated the effects of HuR knockdown on cell growth, apoptosis, and HIF1A expression. We thus conclude that cytoplasmic HuR expression is a marker of poor prognosis in meningioma and that HuR is a promising potential therapeutic target for use in tumours refractory to standard therapies. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Asunto(s)

Biomarcadores de Tumor/metabolismo , Hipoxia de la Célula/fisiología , Proteína 1 Similar a ELAV/metabolismo , Meningioma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/fisiología , Biomarcadores de Tumor/genética , División Celular , Línea Celular Tumoral , Citoplasma/metabolismo , Proteína 1 Similar a ELAV/deficiencia , Proteína 1 Similar a ELAV/genética , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/fisiología , Técnicas de Silenciamiento del Gen , Humanos , Estimación de Kaplan-Meier , Masculino , Meningioma/genética , Meningioma/patología , Persona de Mediana Edad , Clasificación del Tumor , Proteínas de Neoplasias/deficiencia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Variaciones Dependientes del Observador , Pronóstico , Proteínas de Unión al ARN/metabolismo , Estudios Retrospectivos , Regulación hacia Arriba/fisiología