RESUMEN
BACKGROUND AND OBJECTIVES: PTEN hamartoma tumor syndrome (PHTS) is a well-recognized hereditary tumor syndrome and is now also recognized as a common cause of monogenic autism spectrum disorder. There is a vast spectrum of phenotypic variability across individuals with PHTS, and in addition to neurodevelopmental challenges, patients with PHTS may experience a wide variety of neurologic challenges, many of which have only recently been described. Thus, this systematic review aimed to summarize the breadth of the current knowledge of neurologic conditions in individuals with PHTS. METHODS: We conducted a systematic review using the MEDLINE and EMBASE databases until January 2023. We included studies that reported neurologic signs, symptoms, and diagnoses in patients with a diagnosis of PHTS. Two independent reviewers extracted data (neurologic diagnoses and patient details) from each study. Case reports, case series, prospective studies, and therapeutic trials were included. We assessed the quality of evidence using the appropriate tool from the JBI, depending on study design. RESULTS: One thousand nine hundred ninety-six articles were screened, and 90 articles met the inclusion criteria. The majority of the included studies were case reports (49/90, 54%) or small case series (31/90, 34%). Epilepsy secondary to cerebral malformations, neurologic deficits from spinal or cranial arteriovenous malformations, and rare tumors such as dysplastic cerebellar gangliocytoma are among the more severe neurologic features reported across patients with PHTS. One interventional randomized control trial examining neurocognitive endpoints was identified and did not meet its efficacy endpoint. DISCUSSION: Our systematic review defines a broad scope of neurologic comorbidities occurring in individuals with PHTS. Neurologic findings can be categorized by age at onset in individuals with PTHS. Our study highlights the need for additional clinical trial endpoints, informed by the neurologic challenges faced by individuals with PHTS.
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Síndrome de Hamartoma Múltiple , Humanos , Síndrome de Hamartoma Múltiple/genética , Síndrome de Hamartoma Múltiple/complicaciones , Fosfohidrolasa PTEN/genética , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/genéticaRESUMEN
BACKGROUND: A variant can be pathogenic or benign with relation to a human disease. Current classification categories from benign to pathogenic reflect a probabilistic summary of the current understanding. A primary metric of clinical utility for multiplexed assays of variant effect (MAVE) is the number of variants that can be reclassified from uncertain significance (VUS). However, a gap in this measure of utility is that it underrepresents the information gained from MAVEs. The aim of this study was to develop an improved quantification metric for MAVE utility. We propose adopting an information content approach that includes data that does not reclassify variants will better reflect true information gain. We adopted an information content approach to evaluate the information gain, in bits, for MAVEs of BRCA1, PTEN, and TP53. Here, one bit represents the amount of information required to completely classify a single variant starting from no information. RESULTS: BRCA1 MAVEs produced a total of 831.2 bits of information, 6.58% of the total missense information in BRCA1 and a 22-fold increase over the information that only contributed to VUS reclassification. PTEN MAVEs produced 2059.6 bits of information which represents 32.8% of the total missense information in PTEN and an 85-fold increase over the information that contributed to VUS reclassification. TP53 MAVEs produced 277.8 bits of information which represents 6.22% of the total missense information in TP53 and a 3.5-fold increase over the information that contributed to VUS reclassification. CONCLUSIONS: An information content approach will more accurately portray information gained through MAVE mapping efforts than by counting the number of variants reclassified. This information content approach may also help define the impact of guideline changes that modify the information definitions used to classify groups of variants.
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Proteína BRCA1 , Fosfohidrolasa PTEN , Proteína p53 Supresora de Tumor , Humanos , Fosfohidrolasa PTEN/genética , Proteína BRCA1/genética , Proteína p53 Supresora de Tumor/genética , Variación Genética , Biología Computacional/métodosRESUMEN
BACKGROUND: Vasculogenic mimicry (VM) is a potential cause of resistance to antiangiogenic therapy and is closely related to the malignant progression of tumors. It has been shown that noncoding RNAs play an important role in the formation of VM in malignant tumors. However, the role of circRNAs in VM of bladder cancer and the regulatory mechanisms are unclear. METHODS: Firstly, hsa_circ_0000520 was identified to have circular character by Sanger sequencing and Rnase R assays. Secondly, the potential clinical value of hsa_circ_0000520 was explored by quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH) of clinical specimens. Thirdly, the role of hsa_circ_0000520 in bladder cancer invasion, migration, and VM formation was examined by in vivo and in vitro experiments. Finally, the regulatory mechanisms of hsa_circ_0000520 in the malignant progression of bladder cancer were elucidated by RNA binding protein immunoprecipitation (RIP), RNA pulldown, co-immunoprecipitation (co-IP), qRT-PCR, Western blot (WB), and fluorescence co-localization. RESULTS: Hsa_circ_0000520 was characterized as a circular RNA and was lowly expressed in bladder cancer compared with the paracancer. Bladder cancer patients with high expression of hsa_circ_0000520 had better survival prognosis. Functionally, hsa_circ_0000520 inhibited bladder cancer invasion, migration, and VM formation. Mechanistically, hsa_circ_0000520 acted as a scaffold to promote binding of UBE2V1/UBC13 to Lin28a, further promoting the ubiquitous degradation of Lin28a, improving PTEN mRNA stability, and inhibiting the phosphorylation of the PI3K/AKT pathway. The formation of hsa_circ_0000520 in bladder cancer was regulated by RNA binding protein QKI. CONCLUSIONS: Hsa_circ_0000520 inhibits metastasis and VM formation in bladder cancer and is a potential target for bladder cancer diagnosis and treatment.
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Movimiento Celular , Fosfohidrolasa PTEN , Fosfatidilinositol 3-Quinasas , ARN Circular , Proteínas de Unión al ARN , Transducción de Señal , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/metabolismo , Humanos , ARN Circular/genética , ARN Circular/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Transducción de Señal/genética , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Movimiento Celular/genética , Masculino , Animales , Regulación Neoplásica de la Expresión Génica , Metástasis de la Neoplasia , Femenino , Neovascularización Patológica/genética , Ratones Desnudos , Ratones , Persona de Mediana Edad , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: Dysregulation of vascular homeostasis can induce cardiovascular diseases and increase global mortality rates. Although lineage tracing studies have confirmed the pivotal role of modulated vascular smooth muscle cells (VSMCs) in the progression of pathological vascular remodeling, the underlying mechanisms are still unclear. METHODS: The expression of Tudor-SN was determined in VSMCs of artery stenosis, PDGF-BB-treated VSMCs and atherosclerotic plaque. Loss- and gain-of-function approaches were used to explore the role of Tudor-SN in the modulation of VSMCs phenotype both in vivo and in vitro. RESULTS: In this study, we demonstrate that Tudor-SN expression is significantly elevated in injury-induced arteries, atherosclerotic plaques, and PDGF-BB-stimulated VSMCs. Tudor-SN deficiency attenuates, but overexpression aggravates the synthetic phenotypic switching of VSMCs and pathological vascular remodeling. Loss of Tudor-SN also reduces atherosclerotic plaque formation and increases plaque stability. Mechanistically, PTEN, the major regulator of the MAPK and PI3K-AKT signaling pathways, plays a vital role in Tudor-SN-mediated regulation on proliferation and migration of VSMCs. Tudor-SN facilitates the polyubiquitination and degradation of PTEN via NEDD4-1, thus exacerbating vascular remodeling under pathological conditions. BpV (HOpic), a specific inhibitor of PTEN, not only counteracts the protective effect of Tudor-SN deficiency on proliferation and migration of VSMCs, but also abrogates the negative effect of carotid artery injury-induced vascular remodeling in mice. CONCLUSIONS: Our findings reveal that Tudor-SN deficiency significantly ameliorated pathological vascular remodeling by reducing NEDD4-1-dependent PTEN polyubiquitination, suggesting that Tudor-SN may be a novel target for preventing vascular diseases.
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Ubiquitina-Proteína Ligasas Nedd4 , Fosfohidrolasa PTEN , Ubiquitinación , Remodelación Vascular , Ubiquitina-Proteína Ligasas Nedd4/metabolismo , Ubiquitina-Proteína Ligasas Nedd4/genética , Animales , Ratones , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Músculo Liso Vascular/metabolismo , Masculino , Miocitos del Músculo Liso/metabolismo , Ratones Endogámicos C57BLRESUMEN
MicroRNAs (miRNAs) are a group of small non-coding RNAs and play an important role in controlling vital biological processes, including cell cycle control, apoptosis, metabolism, and development and differentiation, which lead to various diseases such as neurological, metabolic disorders, and cancer. Chemotherapy consider as gold treatment approaches for cancer patients. However, chemotherapeutic is one of the main challenges in cancer management. Doxorubicin (DOX) is an anti-cancer drug that interferes with the growth and spread of cancer cells. DOX is used to treat various types of cancer, including breast, nervous tissue, bladder, stomach, ovary, thyroid, lung, bone, muscle, joint and soft tissue cancers. Also recently, miRNAs have been identified as master regulators of specific genes responsible for the mechanisms that initiate chemical resistance. miRNAs have a regulatory effect on chemotherapy resistance through the regulation of apoptosis process. Also, the effect of miRNAs p53 gene as a key tumor suppressor was confirmed via studies. miRNAs can affect main biological pathways include PI3K pathway. This review aimed to present the current understanding of the mechanisms and effects of miRNAs on apoptosis, p53 and PTEN/PI3K/Akt signaling pathway related to DOX resistance.
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Doxorrubicina , Resistencia a Antineoplásicos , MicroARNs , Neoplasias , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/genética , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Apoptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Animales , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genéticaRESUMEN
The phosphatase and tensin homolog (PTEN) gene acts as a tumor suppressor by regulating the PI3K/AKT pathway, crucial for cell growth and survival. Mutations or loss of PTEN are common in breast cancer, leading to uncontrolled cell growth. Understanding PTEN's role is vital for targeted therapies. 276 formalin-fixed paraffin-embedded (FFPE) breast cancer tissue blocks from 2012 to 2016 were analyzed for PTEN expression. Immunohistochemistry was performed to identify and assess tumor related clinicopathological characteristics as well as patient demographics. These were statistically matched with PTEN expression. Only 27.5% of the breast cancer tumors were PTEN-positive. PTEN expression correlated significantly with smaller tumor size, lower tumor grade, positive estrogen and progesterone receptor status, and favorable/unfavorable Ki67 status (p < 0.001). No significant association was found with vascular invasion, histologic type, age, HER2 status, staging, or lymph node involvement (p > 0.05). The study confirms PTEN's association with favorable clinicopathological features in breast cancer, supporting its role as a prognostic marker. These findings underscore the importance of PTEN in breast cancer biology and its potential as a therapeutic target. Furthermore these findings confirm the prevalence of advanced stage and aggressive breast cancer tumors in Ghana.
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Biomarcadores de Tumor , Neoplasias de la Mama , Fosfohidrolasa PTEN , Humanos , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Pronóstico , Inmunohistoquímica , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Pulmonary fibrosis (PF) is an aging-related progressive lung disorder. The aged lung undergoes functional and structural changes termed immunosenescence and inflammaging, which facilitate the occurrence of fibrosis. Interleukin-10 (IL-10) is a potent anti-inflammatory and immunoregulatory cytokine, yet it remains unclear how IL-10 deficiency-induced immunosenescence participates in the development of PF. METHODS: Firstly we evaluated the susceptibility to fibrosis and IL-10 expression in aged mice. Then 13-month-old wild-type (WT) and IL-10 knockout (KO) mice were subjected to bleomycin(BLM) and analyzed senescence-related markers by PCR, western blot and immunohistochemistry staining of p16, p21, p53, as well as DHE and SA-ß-gal staining. We further compared 18-month-old WT mice with 13-month-old IL-10KO mice to assess aging-associated cell senescence and inflamation infiltration in both lung and BALF. Moreover, proliferation and apoptosis of alveolar type 2 cells(AT2) were evaluated by FCM, immunofluorescence, TUNEL staining, and TEM analysis. Recombinant IL-10 (rIL-10) was also administered intratracheally to evaluate its therapeutic potential and related mechanism. For the in vitro experiments, 10-week-old naïve pramily lung fibroblasts(PLFs) were treated with the culture medium of 13-month PLFs derived from WT, IL-10KO, or IL-10KO + rIL-10 respectively, and examined the secretion of senescence-associated secretory phenotype (SASP) factors and related pathways. RESULTS: The aged mice displayed increased susceptibility to fibrosis and decreased IL-10 expression. The 13-month-old IL-10KO mice exhibited significant exacerbation of cell senescence compared to their contemporary WT mice, and even more severe epithelial-mesenchymal transition (EMT) than that of 18 month WT mice. These IL-10 deficient mice showed heightened inflammatory responses and accelerated PF progression. Intratracheal administration of rIL-10 reduced lung CD45 + cell infiltration by 15%, including a 6% reduction in granulocytes and a 10% reduction in macrophages, and increased the proportion of AT2 cells by approximately 8%. Additionally, rIL-10 significantly decreased α-SMA and collagen deposition, and reduced the expression of senescence proteins p16 and p21 by 50% in these mice. In vitro analysis revealed that conditioned media from IL-10 deficient mice promoted SASP secretion and upregulated senescence genes in naïve lung fibroblasts, which was mitigated by rIL-10 treatment. Mechanistically, rIL-10 inhibited TGF-ß-Smad2/3 and PTEN/PI3K/AKT/ERK pathways, thereby suppressing senescence and fibrosis-related proteins. CONCLUSIONS: IL-10 deficiency in aged mice leads to accelerated cell senescence and exacerbated fibrosis, with IL-10KO-PLFs displaying increased SASP secretion. Recombinant IL-10 treatment effectively mitigates these effects, suggesting its potential as a therapeutic target for PF.
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Bleomicina , Senescencia Celular , Interleucina-10 , Ratones Noqueados , Fosfohidrolasa PTEN , Proteínas Proto-Oncogénicas c-akt , Fibrosis Pulmonar , Animales , Interleucina-10/metabolismo , Interleucina-10/genética , Ratones , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Ratones Endogámicos C57BL , Sistema de Señalización de MAP Quinasas , Apoptosis , Pulmón/patología , Pulmón/metabolismo , Masculino , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/patología , Modelos Animales de Enfermedad , Proliferación Celular , Envejecimiento , Transducción de SeñalRESUMEN
Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a rare overgrowth condition caused by a pathogenic variant in the phosphatase and tensin homolog (PTEN) gene and belongs to a group of disorders called PTEN hamartoma tumor syndrome (PHTS). The diagnosis is often complicated by great phenotypic diversity. Furthermore, to this date treatment options are limited. Here we performed a systematic review using PubMed, Cochrane, and Scopus databases to identify cases of pediatric patients diagnosed with BRRS and summarized information about the clinical presentation, treatment, and long-term patient care. A total of 83 pediatric patients with BRRS were identified. The most common clinical findings were macrocephaly (77%) and developmental disorders (63%). Surgical interventions were the treatment of choice, described in 19 articles. Patient surveillance was proposed in 15 case reports and mostly aimed at periodic cancer screening. Recognition of BRRS clinical symptoms and early referral to a geneticist is important for better disease control and overall prognosis. As targeted treatment is still lacking, symptom relief and long-term surveillance remain the main management strategies.
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Síndrome de Hamartoma Múltiple , Fosfohidrolasa PTEN , Humanos , Síndrome de Hamartoma Múltiple/genética , Síndrome de Hamartoma Múltiple/patología , Síndrome de Hamartoma Múltiple/diagnóstico , Fosfohidrolasa PTEN/genética , Niño , Femenino , Masculino , Preescolar , Adolescente , LactanteRESUMEN
Naïve pluripotency is sustained by a self-reinforcing gene regulatory network (GRN) comprising core and naïve pluripotency-specific transcription factors (TFs). Upon exiting naïve pluripotency, embryonic stem cells (ESCs) transition through a formative post-implantation-like pluripotent state, where they acquire competence for lineage choice. However, the mechanisms underlying disengagement from the naïve GRN and initiation of the formative GRN are unclear. Here, we demonstrate that phosphorylated AKT acts as a gatekeeper that prevents nuclear localisation of FoxO TFs in naïve ESCs. PTEN-mediated reduction of AKT activity upon exit from naïve pluripotency allows nuclear entry of FoxO TFs, enforcing a cell fate transition by binding and activating formative pluripotency-specific enhancers. Indeed, FoxO TFs are necessary and sufficient for the activation of the formative pluripotency-specific GRN. Our work uncovers a pivotal role for FoxO TFs in establishing formative post-implantation pluripotency, a critical early embryonic cell fate transition.
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Redes Reguladoras de Genes , Células Madre Pluripotentes , Animales , Ratones , Células Madre Pluripotentes/metabolismo , Diferenciación Celular/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Fosforilación , Células Madre Embrionarias de Ratones/metabolismo , Células Madre Embrionarias/metabolismo , Regulación del Desarrollo de la Expresión GénicaRESUMEN
On chromosome 10q23 is found the PTEN gene, which encodes a phosphate and tension homologue. The protein dephosphorylates phosphatidylinositol-(3,4,5)-trisphosphate at the plasma membrane to produce inorganic phosphatidylinositol-(4,5)-bisphosphate. This enzymatic activity inhibits the phosphatidylinositol-3-kinase, protein kinase B and mammalian target of the rapamycin signalling cascade. Consequently, essential cellular functions, including metabolic regulation, cellular growth, proliferation and viability, are affected. A mutation in this gene gives rise to hamartoma tumour syndrome, which exhibits a range of phenotypes, including Bannayan-Riley-Ruvalcaba syndrome, Cowden syndrome and proteus-like disease. A man in his late 20s with a PTEN tumour-like arteriovenous malformation in the right thigh was recently diagnosed with lupus nephritis. The patient's nephritic symptoms, pleural effusion, dyslipidaemia and splenomegaly demonstrate systemic lupus erythematosus (SLE) multisystem involvement. The case report identifies an association between a PTEN mutation and a new diagnosis of SLE that might have been triggered by PTEN-associated immune dysregulation.
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Síndrome de Hamartoma Múltiple , Nefritis Lúpica , Fosfohidrolasa PTEN , Humanos , Masculino , Fosfohidrolasa PTEN/genética , Síndrome de Hamartoma Múltiple/genética , Síndrome de Hamartoma Múltiple/complicaciones , Nefritis Lúpica/genética , Nefritis Lúpica/complicaciones , Mutación , AdultoRESUMEN
The mechanisms underlying the sustained activation of the PI3K/AKT and Wnt/ß-catenin pathways mediated by HOTAIR in cervical cancer (CC) have not been extensively described. To address this knowledge gap in the literature, we explored the interactions between these pathways by driving HOTAIR expression levels in HeLa cells. Our findings reveal that HOTAIR is a key regulator in sustaining the activation of both signaling pathways. Specifically, altering HOTAIR expression-either by knockdown or overexpression-significantly influenced the transcriptional activity of the PI3K/AKT and Wnt/ß-catenin pathways. Additionally, we discovered that HIF1α directly induces HOTAIR transcription, which in turn leads to the epigenetic silencing of the PTEN promoter via DNMT1. This process leads to the sustained activation of both pathways, highlighting a novel regulatory axis involving HOTAIR and HIF1α in cervical cancer. Our results suggest a new model in which HOTAIR sustains reciprocal activation of the PI3K/AKT and Wnt/ß-catenin pathways through the HOTAIR/HIF1α axis, thereby contributing to the oncogenic phenotype of cervical cancer.
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Metilación de ADN , Subunidad alfa del Factor 1 Inducible por Hipoxia , Fosfohidrolasa PTEN , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , ARN Largo no Codificante , Neoplasias del Cuello Uterino , Vía de Señalización Wnt , Humanos , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Femenino , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Vía de Señalización Wnt/genética , Células HeLa , Metilación de ADN/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Regulación Neoplásica de la Expresión Génica , beta Catenina/metabolismo , beta Catenina/genética , Regiones Promotoras Genéticas/genética , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/genéticaAsunto(s)
Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Humanos , Masculino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/cirugía , Persona de Mediana Edad , Astrocitoma/genética , Astrocitoma/metabolismo , Astrocitoma/patología , Astrocitoma/cirugía , Glioblastoma/patología , Glioblastoma/genética , Glioblastoma/cirugía , Glioblastoma/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Mutación , Isocitrato Deshidrogenasa/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/genética , Factor de Transcripción 2 de los Oligodendrocitos/metabolismoRESUMEN
Diabetic peripheral neuropathy (DPN) is a common nerve-damaging complication of diabetes mellitus. Effective treatments are needed to alleviate and reverse diabetes-associated damage to the peripheral nerves. Curcumin is an effective neuroprotectant that plays a protective role in DPN promoted by Schwann cells (SCs) lesions. However, the potential molecular mechanism of curcumin remains unclear. Therefore, our aim is to study the detailed molecular mechanism of curcumin-mediated SCs repair in order to improve the efficacy of curcumin in the clinical treatment of DPN. First, candidate target genes of curcumin in rat SC line RSC96 cells stimulated by high glucose were identified by RNA sequencing and bioinformatic analyses. Enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was carried out by Metascape, followed by 8 algorithms on Cytoscape to determine 4 hub genes, namly Hmox1, Pten, Vegfa and Myc. Next, gene set enrichment analysis (GSEA) and Pearson function showed that Hmox1 was significantly correlated with apoptosis. Subsequently, qRT-PCR, MTT assay, flow cytometry, caspase-3 activity detection and westernblot showed that curcumin treatment increased RSC96 cell viability, reduced cell apoptosis, increased Hmox1, Pten, Vegfa and Myc expression, and up-regulated Akt phosphorylation level under high glucose environment. Finally, molecular docking predicted the binding site of curcumin to Hmox1. These results suggest that curcumin can reduce the apoptosis of SCs induced by high glucose, and Hmox1 is a potential target for curcumin. Our findings provide new insights about the mechanism of action of curcumin on SC as a potential treatment in DPN.
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Biología Computacional , Curcumina , Neuropatías Diabéticas , Células de Schwann , Curcumina/farmacología , Animales , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/metabolismo , Ratas , Células de Schwann/efectos de los fármacos , Células de Schwann/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular , Simulación del Acoplamiento Molecular , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Glucosa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Supervivencia Celular/efectos de los fármacos , Fármacos Neuroprotectores/farmacologíaRESUMEN
OBJECTIVE: To investigate the role of Parkin overexpression-induecd mitophagy in alleviating acute lung injury of exertional heat stroke(EHS) rats. METHODS: Eighty SD rats were divided into four groups: Control group (CON group), Control Parkin overexpression group (CON + Parkin group), exertional heat stroke group (EHS group), and exertional heat stroke Parkin overexpression group (EHS + Parkin group). Adeno-associated virus carrying the Parkin gene was intravenously injected into the rats to overexpress Parkin in the lung tissue. An exertional heat stroke rat model was established, and survival curves were plotted. Lung Micro-CT was performed, and lung coefficient and pulmonary microvascular permeability were measured. Enzyme-linked immunosorbent assays(ELISA) were used to determine the levels of interleukin-6(IL-6), interleukin-1ß(IL-1ß), Tumor necrosis factor-α(TNF-α), and reactive oxygen species(ROS). The morphology of mitochondria in type II epithelial cells of lung tissue was observed using transmission electron microscopy. The apoptosis of lung tissue, the level of mitophagy, and the co-localization of Pink1 and Parkin were determined using immunofluorescence. The expression of Pink1, Parkin, MFN2, PTEN-L, PTEN, p62, and microtubule associated protein 1 light chain 3 (LC3) in rat lung tissue was measured by western blot. RESULTS: Compared with the CON group, there were more severe lung injury and more higher levels of IL-6, IL-1ß, TNF-α in EHS rats. Both of the LC3-II/LC3-I ratio and the co-localization of LC3 and Tom20 in the lung tissue of EHS rats decreased. Compared with the EHS group, the survival rate of rats in the EHS + Parkin overexpression group was significantly increased, lung coefficient and pulmonary microvascular permeability were reduced, and pathological changes such as exudation and consolidation were significantly alleviated. The levels of IL-6, IL-1ß, TNF-α, and ROS were significantly decreased; the degree of mitochondrial swelling in type II alveolar epithelial cells was reduced, and no vacuolization was observed. Lung tissue apoptosis was reduced, and the colocalization fluorescence of Pink1 and Parkin, as well as LC3 and Tom20, were increased. The expression of Parkin and LC3-II/LC3-I ratio in lung tissue were both increased, while the expression of P62, Pink1, MFN2, and PTEN-L was decreased. CONCLUSION: Pink1/Parkin-mediated mitophagy dysfunction is one of the mechanisms underlying acute lung injury in rats with EHS, and activation of Parkin overexpression induced-mitophagy can alleviate acute lung injury caused by EHS.
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Lesión Pulmonar Aguda , Golpe de Calor , Pulmón , Mitofagia , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno , Ubiquitina-Proteína Ligasas , Animales , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Golpe de Calor/metabolismo , Golpe de Calor/complicaciones , Golpe de Calor/patología , Ratas , Pulmón/metabolismo , Pulmón/patología , Masculino , Lesión Pulmonar Aguda/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Modelos Animales de Enfermedad , Proteínas Quinasas/metabolismo , Proteínas Quinasas/genética , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-1beta/metabolismo , Apoptosis , Interleucina-6/metabolismo , Interleucina-6/genética , Mitocondrias/metabolismo , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genéticaRESUMEN
It is well known how the precise localization of glioblastoma multiforme (GBM) predicts the direction of tumor spread in the surrounding neuronal structures. The aim of the present review is to reveal the lateralization of GBM by evaluating the anatomical regions where it is frequently located as well as the main molecular alterations observed in different brain regions. According to the literature, the precise or most frequent lateralization of GBM has yet to be determined. However, it can be said that GBM is more frequently observed in the frontal lobe. Tractus and fascicles involved in GBM appear to be focused on the corticospinal tract, superior longitudinal I, II and III fascicles, arcuate fascicle long segment, frontal strait tract, and inferior frontooccipital fasciculus. Considering the anatomical features of GBM and its brain involvement, it is logical that the main brain regions involved are the frontaltemporalparietaloccipital lobes, respectively. Although tumor volumes are higher in the right hemisphere, it has been determined that the prognosis of patients diagnosed with cancer in the left hemisphere is worse, probably reflecting the anatomical distribution of some detrimental alterations such as TP53 mutations, PTEN loss, EGFR amplification, and MGMT promoter methylation. There are theories stating that the right hemisphere is less exposed to external influences in its development as it is responsible for the functions necessary for survival while tumors in the left hemisphere may be more aggressive. To shed light on specific anatomical and molecular features of GBM in different brain regions, the present review article is aimed at describing the main lateralization pathways as well as gene mutations or epigenetic modifications associated with the development of brain tumors.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Glioblastoma/genética , Glioblastoma/patología , Glioblastoma/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Mutación , Glioma/genética , Glioma/patología , Glioma/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Pronóstico , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/metabolismoRESUMEN
BACKGROUND: Infantile Juvenile polyposis of infantile (JPI) is a rare and aggressive form of juvenile polyposis syndrome (JPS) typically diagnosed in the first year of life. It often carries a poor prognosis due to chronic gastrointestinal bleeding, protein-losing enteropathy, malnutrition and immune deficiency. CASE PRESENTATION: We report a case of a girl initially presented with pallor at 7 months of age, which progressed to gastrointestinal bleeding and protein-losing enteropathy. Endoscopic examination, which included both upper gastrointestinal endoscopy and enteroscopy, showed diffuse polyposis. Histopathology results indicated the presence of juvenile polyps with no dysplasia in all removed polyps. Genetic testing identified a 2.1 Mb deletion on chromosome 10q23.2q23.31 involving the phosphatase and tensin homolog (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A) genes. Treatment with sirolimus initiated at 10 months of age led to a reduction in the need for blood and albumin infusions, improved patient growth, and quality of life. While the frequency of endoscopic evaluations decreased with sirolimus, regular endoscopic polypectomy every 5 months remained necessary. However, discontinuation of sirolimus resulted in polyp recurrence after 2 months due to pneumonia. CONCLUSION: This case highlights sirolimus treatment can alleviate many complications of JPI, it does not eliminate the need for aggressive polypectomy.
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Poliposis Intestinal , Sirolimus , Humanos , Femenino , Sirolimus/uso terapéutico , Poliposis Intestinal/congénito , Poliposis Intestinal/genética , Poliposis Intestinal/tratamiento farmacológico , Poliposis Intestinal/diagnóstico , Lactante , Síndromes Neoplásicos Hereditarios/tratamiento farmacológico , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Inmunosupresores/uso terapéutico , Fosfohidrolasa PTEN/genéticaRESUMEN
Late endosomal/lysosomal adaptor, MAPK and mTOR, or LAMTOR, is a scaffold protein complex that senses nutrients and integrates growth factor signaling. The role of LAMTOR4 in tumorigenesis is still unknown. However, there is a considerable possibility that LAMTOR4 is directly involved in tumor cell proliferation and metastasis. In the current study, we investigated the protein expression of LAMTOR4 in a cohort of 314 men who were undergoing transurethral resection of prostate (TURP) consisting of incidental, advanced and castration-resistant cases. We also correlated the data with ERG and PTEN genomic status and clinicopathological features including Gleason score and patients' outcome. Additionally, we performed in vitro experiments utilizing knockdown of LAMTOR4 in prostate cell lines, and we performed mRNA expression assessment using TCGA prostate adenocarcinoma (TCGA-PRAD) to explore the potential differentially expressed genes and pathways associated with LAMTOR4 overexpression in PCa patients. Our data indicate that high LAMTOR4 protein expression was significantly associated with poor overall survival (OS) (HR: 1.44, CI: 1.01-2.05, p = 0.047) and unfavorable cause-specific survival (CSS) (HR: 1.71, CI: 1.06-2.77, p = 0.028). Additionally, when high LAMTOR4 expression was combined with PTEN-negative cases (score 0), we found significantly poorer OS (HR: 2.22, CI: 1.37-3.59, p = 0.001) and CSS (HR: 3.46, CI: 1.86-6.46, p < 0.0001). Furthermore, ERG-positive cases with high LAMTOR4 exhibited lower OS (HR: 1.98, CI: 1.18-3.31, p = 0.01) and CSS (HR: 2.54, CI: 1.32-4.87, p = 0.005). In vitro assessment showed that knockdown of LAMTOR4 decreases PCa cell proliferation, migration, and invasion. Our data further showed that knockdown of LAMTOR4 in the LNCaP cell line significantly dysregulated the ß catenin/mTOR pathway and tumorigenesis associated pathways. Inhibiting components of the mTOR pathway, including LAMTOR4, might offer a strategy to inhibit tumor progression and metastasis in prostate cancer.
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Proteínas Adaptadoras Transductoras de Señales , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata , Humanos , Masculino , Proliferación Celular/genética , Movimiento Celular/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Línea Celular Tumoral , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Anciano , Invasividad Neoplásica , Técnicas de Silenciamiento del Gen , Persona de Mediana Edad , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , PronósticoRESUMEN
It is well established that microRNA-21 (miR-21) targets phosphatase and tensin homolog (PTEN), facilitating epithelial-to-mesenchymal transition (EMT) and drug resistance in cancer. Recent evidence indicates that PTEN activates its pseudogene-derived long non-coding RNA, PTENP1, which in turn inhibits miR-21. However, the dynamics of PTEN, miR-21, and PTENP1 in the DNA damage response (DDR) remain unclear. Thus, we propose a dynamic Boolean network model by integrating the published literature from various cancers. Our model shows good agreement with the experimental findings from breast cancer, hepatocellular carcinoma (HCC), and oral squamous cell carcinoma (OSCC), elucidating how DDR activation transitions from the intra-S phase to the G2 checkpoint, leading to a cascade of cellular responses such as cell cycle arrest, senescence, autophagy, apoptosis, drug resistance, and EMT. Model validation underscores the roles of PTENP1, miR-21, and PTEN in modulating EMT and drug resistance. Furthermore, our analysis reveals nine novel feedback loops, eight positive and one negative, mediated by PTEN and implicated in DDR cell fate determination, including pathways related to drug resistance and EMT. Our work presents a comprehensive framework for investigating cellular responses following DDR, underscoring the therapeutic potential of targeting PTEN, miR-21, and PTENP1 in cancer treatment.
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Daño del ADN , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , MicroARNs , Fosfohidrolasa PTEN , ARN Largo no Codificante , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Transición Epitelial-Mesenquimal/genética , Resistencia a Antineoplásicos/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/tratamiento farmacológico , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Apoptosis/genética , Transducción de SeñalRESUMEN
Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in the glandular epithelium of KrasG12D;Pik3caH1047R or Trp53R172H and/or ablation of Pten or Trp53. We find that KrasG12D;Pik3caH1047R is sufficient to induce adenomas and that lesions progress to carcinoma when also harboring Pten deletions. An additional challenge with either Trp53 loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling in response to gp130 family cytokines remained as a gatekeeper for all stages of tumor development, metastatic progression required a mutant Trp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with the poorer survival of patients with high IL-6 expression, we identify IL-6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer.
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Progresión de la Enfermedad , Interleucina-6 , Factor de Transcripción STAT3 , Neoplasias Gástricas , Proteína p53 Supresora de Tumor , Animales , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Interleucina-6/metabolismo , Interleucina-6/genética , Ratones , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Mutación/genética , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Interleucina-11/metabolismo , Interleucina-11/genéticaRESUMEN
Intrinsic resistance to targeted therapeutics in PTEN-deficient glioblastoma (GBM) is mediated by redundant signaling networks that sustain critical metabolic functions. Here, we demonstrate that coordinated inhibition of the ribosomal protein S6 kinase 1 (S6K1) and the receptor tyrosine kinase AXL using LY-2584702 and BMS-777607 can overcome network redundancy to reduce GBM tumor growth. This combination of S6K1 and AXL inhibition suppressed glucose flux to pyrimidine biosynthesis. Genetic inactivation studies to map the signaling network indicated that both S6K1 and S6K2 transmit growth signals in PTEN-deficient GBM. Kinome-wide ATP binding analysis in inhibitor-treated cells revealed that LY-2584702 directly inhibited S6K1, and substrate phosphorylation studies showed that BMS-777607 inactivation of upstream AXL collaborated to reduce S6K2-mediated signal transduction. Thus, combination targeting of S6K1 and AXL provides a kinase-directed therapeutic approach that circumvents signal transduction redundancy to interrupt metabolic function and reduce growth of PTEN-deficient GBM. SIGNIFICANCE: Therapy for glioblastoma would be advanced by incorporating molecularly targeted kinase-directed agents, similar to standard of care strategies in other tumor types. Here, we identify a kinase targeting approach to inhibit the metabolism and growth of glioblastoma.