RESUMEN
BACKGROUND: Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a complex disorder. Carriers develop hamartomatous tumors, with an increased risk for developing malignant tumors in multiple organs. Surveillance to facilitate the early detection and treatment of malignancies is extremely important. CASE REPORT: A 31-year-old male presented with a 10 cm left lobe thyroid gland mass. After fine needle aspiration a left hemithyroidectomy was performed, which demonstrated a minimally invasive follicular thyroid carcinoma (FTC, stage pT3a) and microscopic classical papillary thyroid carcinoma (PTC) in the background of about 50 separate adenomatous nodules (0.2-5 mm). Immunostaining showed loss of PTEN protein in the minimally invasive FTC and in all of the nodules tested, with uninvolved parenchyma serving as an internal control. Kaiser Permanente Northern California (KPNC) Hereditary Cancer Panel, testing for 62 genes, was performed and showed germline mutations in PTEN and RecQ like helicase 4 (RECQL4) genes. Completion thyroidectomy subsequently performed demonstrated about 60 follicular cell-derived adenomatous nodules (0.3-10 mm). Genetic counseling and evaluation documented Cowden syndrome (CS) in the family. Thus, PHTS was confirmed. CONCLUSION: This report documents synchronous FTC and PTC in a background of multiple follicular adenomatous nodules with a novel RECQL4 mutation in an adult patient with PHTS. As such, documented the loss of PTEN protein in a thyroid gland affected by multiple adenomatous nodules aided in diagnosing PHTS.
Asunto(s)
Adenocarcinoma Folicular/genética , Biomarcadores de Tumor/genética , Carcinoma Papilar/genética , Análisis Mutacional de ADN , Mutación de Línea Germinal , Síndrome de Hamartoma Múltiple/genética , RecQ Helicasas/genética , Neoplasias de la Tiroides/genética , Adenocarcinoma Folicular/enzimología , Adenocarcinoma Folicular/patología , Adenocarcinoma Folicular/cirugía , Adulto , Biomarcadores de Tumor/análisis , Biopsia con Aguja Fina , Carcinoma Papilar/enzimología , Carcinoma Papilar/patología , Carcinoma Papilar/cirugía , Predisposición Genética a la Enfermedad , Síndrome de Hamartoma Múltiple/enzimología , Síndrome de Hamartoma Múltiple/patología , Síndrome de Hamartoma Múltiple/cirugía , Humanos , Inmunohistoquímica , Masculino , Fosfohidrolasa PTEN/análisis , Fenotipo , Valor Predictivo de las Pruebas , Neoplasias de la Tiroides/enzimología , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/cirugía , TiroidectomíaRESUMEN
AIMS: Although several studies have evaluated PTEN loss in Prostatic Adenocarcinoma (PCa), PTEN loss correlation with different histological patterns only has a few studies. Although several studies have evaluated PD-L1 expression in PCa and its correlation with Gleason scores, as far as we know, there are no prior studies that have included a comparison between PD-L1 expression and histological patterns of PCa. This study aims to evaluate PTEN loss and PD-L1 expression by immunohistochemistry in different histological patterns of PCa. METHODS: The current study included consecutive 98 radical prostatectomy specimens with 151 foci with different Gleason Grade (GG) patterns. RESULTS: The highest frequency of PTEN loss was observed in GG4 cribriform and glomeruloid patterns (59.3%, p < 0.001). Combined score (CS) PD-L1 positivity was observed in fourteen patients (14.2%). Tumor cell (TC) and tumor-associated inflammatory cells (IC) PD-L1 positivity was observed in 10 (10.2%) and 7 (7.1%) patients. The highest frequency of PD-L1 expression was observed in the GG5 pattern, and between GG4 patterns, the irregular pattern had the highest PD-L1 positivity. CONCLUSIONS: In conclusion, in our cohort of consecutive unselected cases of prostatic carcinoma, we observed the highest PTEN loss rate in the GG4 cribriform and glomeruloid pattern and the highest PD-L1 expression rate in the GG5 and GG4 irregular patterns. These results may predict molecular differences between different histological patterns in PCa and may be used to inform a treatment decision. Future studies should investigate these differences between histological patterns of PCa to predict response to immunotherapy in larger cohorts.
Asunto(s)
Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Antígeno B7-H1/biosíntesis , Fosfohidrolasa PTEN/biosíntesis , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Adenocarcinoma/química , Antígeno B7-H1/análisis , Humanos , Masculino , Fosfohidrolasa PTEN/análisis , Neoplasias de la Próstata/química , Estudios RetrospectivosRESUMEN
BACKGROUND: Phosphatase and tensin homolog (PTEN) loss is associated with tumorigenesis, tumor progression, and therapy resistance in breast cancer. However, the clinical value of PTEN as a biomarker in these patients is controversial. We sought to determine whether the benefit of traditional biomarkers testing is improved by the analysis of PTEN status for the identification of high-risk breast cancer. METHODS: A cohort of 608 patients with breast cancer was included in this study. Based on the expression on the neoplastic cells compared to the normal internal controls by immunohistochemistry (IHC), cases were classified as PTEN-low (PTEN-L) or PTEN-retained (PTEN-WT). The former constituted the study group, while the latter the control group. Analysis of gene expression was performed on publicly available genomic data and included 4265 patients from the METABRIC and MSK cohorts retrieved from cBioPortal. The Shapiro-Wilk test was used to analyze the normal distributions of continuous variables. Relationships between PTEN status and the clinicopathologic and molecular features of the patient population were assessed using Fisher's exact test or Chi-squared/Wilcoxon rank-sum test. Survival curves were built according to the Kaplan-Meier method. RESULTS: Alteration in PTEN status was significantly different at protein and gene levels, where the reduced protein expression was observed in 280/608 cases (46.1%) from our group, while genetic aberrations in only 315/4265 (7.4%) cases of the METABRIC and MSK cohorts. PTEN-L tumors were significantly enriched for hormone receptors (HR) and HER2 negativity (n = 48, 17.1%) compared to PTEN-WT tumors (n = 22, 6.7%; p = 0.0008). Lack of HR with or without HER2 overexpression/amplification was significantly associated with worse overall survival (OS) in PTEN-L but not in PTEN-WT breast cancers (p < .0001). Moreover, PTEN-L protein expression but not gene alterations was related to the outcome, in terms of both OS and disease-free survival (p = 0.002). CONCLUSIONS: The combined analysis of PTEN, HER2, and HR status offers relevant information for a more precise risk assessment of patients with breast cancer.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/química , Fosfohidrolasa PTEN/análisis , Receptor ErbB-2/análisis , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Progresión de la Enfermedad , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Factores de Riesgo , Análisis de Matrices TisularesRESUMEN
The novel anti-neoplastic glycopeptide T11TS retards glioma both in in-vitro clinical samples and in-vivo models. This study investigates the correlation between altering the glioma microenvironment with glioma arrest and death. Flow cytometry, immunoblotting, ELISA, and co-immunoprecipitation were employed to investigate glioma cell arrest and death. Results include a decline in phosphorylation of Akt and attenuation of p21 phosphorylation (Thr145,Ser146) and disassociation of p-Akt-Mdm2 and p-Akt-BAD facilitating death by Akt>BAD. T11TS influence phosphorylation patterns in two focal axes Akt>p21 and Akt>Mdm2>p53. The current article provides crucial insight in deciphering the mechanism of T11TS induced glioma cell arrest and death.
Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Antígenos CD58/farmacología , Glioma/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Antígenos CD58/uso terapéutico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Femenino , Glioma/metabolismo , Glioma/patología , Masculino , Fosfohidrolasa PTEN/análisis , Fosforilación , Proteínas Proto-Oncogénicas c-mdm2/análisis , Ratas , Ratas Wistar , Microambiente Tumoral , Proteína p53 Supresora de Tumor/análisis , Proteína Letal Asociada a bcl/metabolismoRESUMEN
Endometrial carcinoma is one of the most common gynecological cancers. MicroRNA-21 (miR-21) is the most consistently overexpressed miRNA in almost all human cancer types, and it might be a useful clinical biomarker and therapeutic target. However, its precise localization and significance in endometrial carcinoma have not been clarified. This study aimed to examine miR-21 expression in endometrial carcinoma and reveal its clinicopathological importance. We investigated miR-21 expression by in situ hybridization (ISH) using locked nucleic acid (LNA)-modified probes in 230 endometrial carcinoma patients. We evaluated miR-21 expression in cancer cells and stroma separately. High miR-21 expression in cancer cells was significantly associated with higher histological grade and lymph node metastasis. In Kaplan-Meier analysis, high miR-21 expression in cancer cells was significantly associated with poor progression-free survival. In particular, in endometrioid carcinoma, high miR-21 expression in cancer cells was an independent prognostic factor associated with poor progression-free survival, as well as older age and higher International Federation of Gynecology and Obstetrics (FIGO) stage.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma Endometrioide/genética , Neoplasias Endometriales/genética , MicroARNs/genética , Factores de Edad , Biomarcadores de Tumor/análisis , Carcinoma Endometrioide/mortalidad , Carcinoma Endometrioide/secundario , Carcinoma Endometrioide/terapia , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/patología , Neoplasias Endometriales/terapia , Femenino , Humanos , Hibridación in Situ , Metástasis Linfática , Persona de Mediana Edad , Clasificación del Tumor , Fosfohidrolasa PTEN/análisis , Reacción en Cadena de la Polimerasa , Supervivencia sin Progresión , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Regulación hacia ArribaRESUMEN
BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who fail to respond to anti-HER2 treatments have poor prognoses. Most trastuzumab-resistant breast cancer cell lines available from biobanks feature either phosphoinositide-3-kinase, catalytic, alpha (PIK3CA) mutation or the loss of phosphatase and tensin homolog (PTEN). However, PIK3CA mutations and/or PTEN loss do not account for most trastuzumab-resistant tumors in humans. METHODS: Breast cancer cells were collected from one patient's malignant ascites. These cells were cultured and maintained to develop a stable cell line, which we named CK-MB-1. We used western blotting to evaluate protein expression. The PIK3CA status of CK-MB-1 cells was analyzed using Sanger sequencing and validated using next-generation sequencing. In vivo, CK-MB-1 xenograft tumor models were developed in zebrafish and immunodeficient mice. RESULTS: CK-MB-1 cells maintained the major characteristics of the parental tumor including HER2 positivity and estrogen receptor negativity. The HER2 gene amplification of CK-MB-1 cells was detected by fluorescence in situ hybridization. The integrity of PTEN was confirmed by its positive protein expression and the absence of gene mutations. No common PIK3CA mutation was detected. Compared with the findings in two other HER2-positive trastuzumab-resistant cell lines, CK-MB-1 cells exhibited greater resistance to trastuzumab, chemotherapeutics, and small-molecule drugs. Trastuzumab resistance in CK-MB-1 cells was confirmed in vivo using the NOD SCID mouse model. CONCLUSIONS: CK-MB-1 cells represent a stable HER2-positive trastuzumab-resistant breast cancer cell line. The resistance of CK-MB-1 cells does not originate from the PTEN or phosphoinositide 3-kinase signaling pathway, which can provide an alternative approach for potential drugs.
Asunto(s)
Neoplasias de la Mama , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I , Resistencia a Antineoplásicos , Fosfohidrolasa PTEN , Receptor ErbB-2 , Adulto , Animales , Antineoplásicos Inmunológicos/farmacología , Ascitis/patología , Western Blotting , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral/química , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/metabolismo , Línea Celular Tumoral/patología , Fosfatidilinositol 3-Quinasa Clase I/análisis , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Células MCF-7 , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mutación , Fosfohidrolasa PTEN/análisis , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/análisis , Trastuzumab/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Pez CebraRESUMEN
Phosphatase and tensin homolog (PTEN) loss is associated with adverse outcomes in prostate cancer and has clinical potential as a prognostic biomarker. The objective of this work was to develop an artificial intelligence (AI) system for automated detection and localization of PTEN loss on immunohistochemically (IHC) stained sections. PTEN loss was assessed using IHC in two prostate tissue microarrays (TMA) (internal cohort, n = 272 and external cohort, n = 129 patients). TMA cores were visually scored for PTEN loss by pathologists and, if present, spatially annotated. Cores from each patient within the internal TMA cohort were split into 90% cross-validation (N = 2048) and 10% hold-out testing (N = 224) sets. ResNet-101 architecture was used to train core-based classification using a multi-resolution ensemble approach (×5, ×10, and ×20). For spatial annotations, single resolution pixel-based classification was trained from patches extracted at ×20 resolution, interpolated to ×40 resolution, and applied in a sliding-window fashion. A final AI-based prediction model was created from combining multi-resolution and pixel-based models. Performance was evaluated in 428 cores of external cohort. From both cohorts, a total of 2700 cores were studied, with a frequency of PTEN loss of 14.5% in internal (180/1239) and external 13.5% (43/319) cancer cores. The final AI-based prediction of PTEN status demonstrated 98.1% accuracy (95.0% sensitivity, 98.4% specificity; median dice score = 0.811) in internal cohort cross-validation set and 99.1% accuracy (100% sensitivity, 99.0% specificity; median dice score = 0.804) in internal cohort test set. Overall core-based classification in the external cohort was significantly improved in the external cohort (area under the curve = 0.964, 90.6% sensitivity, 95.7% specificity) when further trained (fine-tuned) using 15% of cohort data (19/124 patients). These results demonstrate a robust and fully automated method for detection and localization of PTEN loss in prostate cancer tissue samples. AI-based algorithms have potential to streamline sample assessment in research and clinical laboratories.
Asunto(s)
Biomarcadores de Tumor/análisis , Aprendizaje Profundo , Fosfohidrolasa PTEN/análisis , Neoplasias de la Próstata , Algoritmos , Estudios de Cohortes , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Masculino , Análisis de Matrices TisularesRESUMEN
BACKGROUND: Conservative management with progestin is a treatment option for atypical hyperplasia (AH). However, pathologic diagnosis of residual/recurrent lesions is often problematic because of the profound morphologic changes induced by progestin and the lack of established diagnostic criteria for progestin-treated residual AH. METHODS: We conducted a longitudinal study of 265 endometrial biopsies from 54 patients with a history of AH on progestin therapy. Patient outcomes were divided into 3 categories after morphologic review and immunohistochemical staining with phosphatase and tensin homolog (PTEN) and paired box 2 (PAX2): (1) persistent or residual disease; (2) recurrent disease; (3) complete response. All specimens were classified into 3 categories based on morphology: (1) persistent/recurrent disease (nonresponse), (2) morphologically uncertain response, (3) optimally treated (complete response). The staining patterns of PTEN/PAX2 were tracked over time in individual patients and correlated with morphologic findings before and after progestin therapy. RESULTS: Our data showed that aberrant expression patterns of PTEN and/or PAX2 were identified in 48 (88.9%) of the 54 primary biopsies and persisted in persistent/recurrent AH across serial endometrial biopsies (n=99, P<0.00001), while normal PTEN and PAX2 expressions were consistently observed in optimally treated cases (n=84, P<0.00001). More importantly, follow-up biopsies that showed a morphologically uncertain response but a PTEN/PAX2 expression pattern identical to the initial biopsy were significantly correlated with persistent or recurrent disease (n=18, P=0.000182), as evidenced by areas with morphologic features diagnostic of AH on subsequent biopsy. CONCLUSIONS: Biomarker PTEN/PAX2 signatures offer a valuable diagnostic aid to identify residual AH in progestin-treated endometrial samples for which the biomarker status from preprogestin treated AH is known. The findings of this study are promising for a possible future change of diagnostic practice.
Asunto(s)
Biomarcadores de Tumor/análisis , Hiperplasia Endometrial/diagnóstico , Hiperplasia Endometrial/tratamiento farmacológico , Endometrio/efectos de los fármacos , Congéneres de la Progesterona/uso terapéutico , Adulto , Anciano , Biomarcadores/análisis , Endometrio/patología , Femenino , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Factor de Transcripción PAX2/análisis , Fosfohidrolasa PTEN/análisis , Lesiones Precancerosas/diagnóstico , Lesiones Precancerosas/tratamiento farmacológico , RecurrenciaRESUMEN
Chromophobe renal cell carcinoma (chRCC) is a histologically and molecularly distinct class of rare renal tumor. TCGA studies revealed low mutational burden, with only TP53 and PTEN recurrently mutated, and discovered alterations in TERT promoter and in the electron transport chain Complex I genes. However, knowledge on drug targetable genes is limited and treatments at metastatic stage do not follow a molecular rationale. In a large series of 92 chRCC enriched with metastatic cases, we performed an in-depth characterization of mTOR pathway alterations through targeted NGS and immunohistochemistry (IHC) of phospho-S6, tuberin, and PTEN. Mutations in mitochondria, telomere maintenance and other renal cancer related genes and p53 IHC, were also assessed. The impact on metastasis development and disease specific survival was determined, using TCGA-KICH series (n = 65) for validation. mTOR pathway mutations (MTOR, TSC1, TSC2) were present in 17% of primary tumors, most of them being classified as pathogenic. Mutations were associated with positive IHC staining of phospho-S6 and PTEN (P = 0.009 and P = 0.001, respectively) and with chRCC eosinophilic variant (P = 0.039), supporting a biological relevance of the pathway. mTOR pathway mutations were associated with worse clinical outcomes. Survival analysis gave a hazard ratio of 5.5 (P = 0.027), and this association was confirmed in TCGA-KICH (HR = 10.3, P = 0.006). TP53 mutations were enriched in metastatic cases (P = 0.018), and mutations in telomere maintenance genes showed a trend in the same direction. p53 IHC staining pattern was associated with the underlying TP53 defect, and negative PTEN IHC staining (82% of cases) suggested PTEN loss as a chRCC hallmark. In conclusion, our study provides with novel genomic knowledge in chRCC and identifies novel markers of poor survival. Furthermore, this is the first study showing that mTOR pathway mutations correlate with poor prognosis, and may help to identify patients with increased sensitivity to mTOR inhibitors.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Renales/genética , Neoplasias Renales/genética , Mutación , Serina-Treonina Quinasas TOR/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Carcinoma de Células Renales/química , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapia , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Neoplasias Renales/química , Neoplasias Renales/patología , Neoplasias Renales/terapia , Masculino , Persona de Mediana Edad , Fosfohidrolasa PTEN/análisis , Fenotipo , Fosforilación , Proteínas Quinasas S6 Ribosómicas/análisis , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa/análisis , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: Phosphatase and tensin homolog (PTEN) acts as a tumor suppressor gene. Inactivation of PTEN has been reported in various types of cancers. PTEN promoter methylation possibly underlies PTEN inactivation, which results in tumorigenesis. The aim of this study was to investigate whether PTEN promoter methylation contributes to PTEN inactivation in ameloblastoma and its associated protein expression. MATERIAL AND METHODS: In total, 20 fresh-frozen ameloblastoma samples were evaluated for PTEN promoter methylation using methylation-specific polymerase chain reaction (MS-PCR). A subset of 10 paraffin-embedded ameloblastoma samples was examined for PTEN expression through immunohistochemistry. Four primary cultured ameloblastoma cells were investigated for PTEN promoter methylation and PTEN transcriptional expression via reverse transcription PCR. RESULTS: PTEN promoter methylation was detected in 65% (13/20) of the ameloblastoma samples. Of 10 ameloblastoma samples, 4 exhibited reduced PTEN expression. Of 5 samples with methylated PTEN, 3 (60%) were associated with loss of PTEN expression. However, PTEN expression was detected in 4 (80%) of 5 samples with unmethylated PTEN. In addition, 3 (75%) of 4 primary ameloblastoma cell cultures exhibited an inverse correlation between PTEN promoter methylation and PTEN transcription level. CONCLUSIONS: PTEN promoter methylation is found in a number of ameloblastomas but not significantly correlated with loss of PTEN expression. Genetic or epigenetic mechanisms other than PTEN promoter methylation may contribute to PTEN inactivation in ameloblastoma tumor cells
No disponible
Asunto(s)
Humanos , Masculino , Femenino , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Fosfohidrolasa PTEN/análisis , Metilación , Ameloblastoma/metabolismo , Neoplasias Maxilomandibulares/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adhesión en Parafina , Inmunohistoquímica , Neoplasias Maxilomandibulares/genética , Ameloblastoma/genética , Epigénesis GenéticaRESUMEN
Endometrial carcinoma programmed death-ligand 1 (PD-L1) expression in tumor cells (TCs) and tumor-associated inflammatory cells (ICs) have recently been reported in several studies which vary in terms of their cohort size, design, and methodology. We aimed to assess PD-L1 staining in endometrial carcinomas and correlate this with clinical and pathological factors and PTEN, ARID1A, p53, and MMR protein expression. PD-L1 immunohistochemistry was performed on whole tissue sections of all tumor blocks of 59 consecutive unselected endometrial carcinomas between November 2018 and September 2019. TC and IC PD-L1 positivity with a 1% cut-off value was observed in 10.2% and 67.8% of cases, respectively, and with a 5% cut-off value in 3.4% and 42.4% of cases, respectively. TC PD-L1 positivity with both 1% and 5% cut-off values was significantly related to ARID1A loss (p = 0.001 and p = 0.046, respectively). IC PD-L1 positivity with 1% and 5% cut-off values and combined score were significantly associated with MMR protein deficiency (p = 0.041, p = 0.031, and p = 0.028, respectively). Advanced stage tumors exhibited more frequent PD-L1 expression in ICs (p = 0.039). MELF-type myometrial invasion pattern was more common in tumors with ARID1A loss (p = 0.047). We observed higher rates of IC PD-L1 positivity in endometrial carcinomas than documented in prior studies; this may be related to our usage of "recent" paraffin blocks and whole tissue sections of all tumor blocks. There was a much higher PD-L1 expression in the ICs compared to TCs in our cases. We confirm a previously documented association between MMR deficiency and PD-L1 expression and show a novel association between ARID1A loss and PD-L1 expression in endometrial carcinomas. ARID1A loss represents a potential biomarker of immune checkpoint inhibitor response in endometrial carcinoma.
Asunto(s)
Antígeno B7-H1/biosíntesis , Biomarcadores de Tumor/metabolismo , Neoplasias Endometriales/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/biosíntesis , Neoplasias Endometriales/metabolismo , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Fosfohidrolasa PTEN/análisis , Fosfohidrolasa PTEN/biosíntesis , Factores de Transcripción/análisis , Factores de Transcripción/biosíntesis , Proteína p53 Supresora de Tumor/análisis , Proteína p53 Supresora de Tumor/biosíntesisRESUMEN
PTEN, a 3-phosphatase of phosphoinositide, regulates asymmetric PI(3,4,5)P3 signaling for the anterior-posterior polarization and migration of motile cells. PTEN acts through posterior localization on the plasma membrane, but the mechanism for this accumulation is poorly understood. Here we developed an in vitro single-molecule imaging assay with various lipid compositions and use it to demonstrate that the enzymatic product, PI(4,5)P2, stabilizes PTEN's membrane-binding. The dissociation kinetics and lateral mobility of PTEN depended on the PI(4,5)P2 density on artificial lipid bilayers. The basic residues of PTEN were responsible for electrostatic interactions with anionic PI(4,5)P2 and thus the PI(4,5)P2-dependent stabilization. Single-molecule imaging in living Dictyostelium cells revealed that these interactions were indispensable for the stabilization in vivo, which enabled efficient cell migration by accumulating PTEN posteriorly to restrict PI(3,4,5)P3 distribution to the anterior. These results suggest that PI(4,5)P2-mediated positive feedback and PTEN-induced PI(4,5)P2 clustering may be important for anterior-posterior polarization.
Asunto(s)
Membranas/metabolismo , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Polaridad Celular , Células Cultivadas , Dictyostelium/química , Dictyostelium/metabolismo , Retroalimentación Fisiológica/fisiología , Fosfohidrolasa PTEN/análisis , Fosfatidilinositol 4,5-Difosfato/análisis , Unión Proteica , Imagen Individual de Molécula/métodosRESUMEN
OBJECTIVE: To investigate the expression characteristics, correlations with clinical factors, and prognostic values of phosphatase and tensin homolog (PTEN) and Ki-67 in cranial meningiomas. METHODS: The expression of PTEN and Ki-67 at the mRNA level was analyzed in 34 frozen meningiomas. Clinical data collection, follow-up, correlations, and survival analyses were performed. RESULTS: Twenty-two men and 12 women were included in the study, with a median age of 52.72 ± 11.72 years on admission. The average expression levels of PTEN and Ki-67 were 2.71 ± 1.73 and 0.50 ± 0.57, respectively. The World Health Organization grade III meningiomas exhibited significantly lower levels of PTEN (P = 0.037), whereas grade I meningiomas expressed significantly lower levels of Ki-67 (P = 0.001). For recurrent lesions, the mean Ki-67 expression level was 0.97 ± 0.76, which was significantly greater than that of primary meningiomas with a mean value of 0.25 ± 0.13 (P < 0.001). The Ki-67 expression level was positively correlated with the tumor volume (P < 0.01) and negatively correlated with preoperative Karnofsky Performance Status scale (KPS, P < 0.01), postoperative KPS (P < 0.05), and follow-up KPS (P < 0.01). However, the PTEN expression level did not correlate with these variables. Based on the multivariate Cox analysis, Ki-67 expression level (P < 0.001, hazard ratio [HR] 8.16, 95% confidence interval [CI] 2.86-23.29), and PTEN expression level (P = 0.018, HR 0.47, 95% CI 0.25-0.88) were independent prognostic factors for tumor recurrence. Ki-67 (P = 0.001, HR 19.73, 95% CI 3.65-106.61) and PTEN expression levels (P = 0.024, HR 0.36, 95% CI 0.15-0.88) were also independent prognostic factors for mortality. CONCLUSIONS: A low PTEN expression and a high Ki-67 expression could predict malignancy in cranial meningiomas.
Asunto(s)
Biomarcadores de Tumor/análisis , Antígeno Ki-67/biosíntesis , Neoplasias Meníngeas/patología , Meningioma/patología , Fosfohidrolasa PTEN/biosíntesis , Adulto , Anciano , Neoplasias Encefálicas/patología , Femenino , Humanos , Antígeno Ki-67/análisis , Masculino , Persona de Mediana Edad , Fosfohidrolasa PTEN/análisis , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
WW domain containing E3 Ub-protein ligase 2 (WWP2) plays an important role in tumor progression as an E3 ligase of PTEN. Here, we investigated the role of WWP2 in gastric cancer (GC). We found that WWP2 is overexpressed in GC tissues, which is closely related to poor prognosis of GC patients. Using a WWP2-shRNA lentivirus expressing system, we established WWP2 stable-knockdown GC cell lines and found that knockdown of WWP2 inhibits the proliferation of GC cells both in vitro and in vivo. Also, WWP2 silencing induced the up-regulation of PTEN protein level and down-regulation of AKT phosphorylation level. We further investigated the role of PTEN in this regulating process by performing rescue assay and found that PTEN is essential for WWP2-mediated regulation of GC cells proliferation. Taken together, our results demonstrated that WWP2 promotes proliferation of GC cells by downregulating PTEN, which may provide new therapeutic targets for GC.
Asunto(s)
Fosfohidrolasa PTEN/metabolismo , Neoplasias Gástricas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones Desnudos , Fosfohidrolasa PTEN/análisis , Fosfohidrolasa PTEN/genética , Pronóstico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Ubiquitina-Proteína Ligasas/análisis , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Our purpose was to explore the value of 68Ga-prostate-specific membrane antigen (PSMA) PET/CT for detection of phosphatase and tensin homolog (PTEN)-loss prostate cancer. Methods: We retrospectively enrolled 75 patients who underwent multiparametric MRI and 68Ga-PSMA PET/CT before radical prostatectomy. Lesions were outlined on pathologic images, and regions of interest were drawn on matched multiparametric MRI and PET/CT images. Imaging parameters, including average apparent diffusion coefficient and SUVmax, were derived. Immunohistochemical staining was performed to evaluate the PTEN status. The diagnostic performance of imaging parameters was analyzed by receiver-operating-characteristic analysis. Univariate logistic regression analyses were used to evaluate the association between clinical and imaging variables and PTEN status. Results: In total, 103 lesions from 75 patients were analyzed. Of these lesions, 38 of 103 (36.9%) showed PTEN-loss status. Our study showed a strong association between SUVmax and PTEN-loss tumors both in the per-patient analysis (P < 0.01) and in the per-lesion analysis (P < 0.01), yielding sensitivity and specificity of 0.80 and 0.77, respectively, in the per-patient analysis and 0.83 and 0.74, respectively, in the per-lesion analysis. Meanwhile, higher pathologic PSMA expression was found in the PTEN-deficiency tumors. However, there was no significant difference between PTEN-loss tumors and PTEN-intact tumors using parameters such as average apparent diffusion coefficient (P > 0.05) and score on the Prostate Imaging Reporting and Data System, version 2 (P > 0.05). Surprisingly, SUVmax was a significant predictor for detection of PTEN-loss tumors (odds ratio of 7.56 and 95% confidence interval of 2.18-26.24 on per-patient analysis; odds ratio of 13.66 and 95% confidence interval of 4.32-43.24 on per-lesion analysis). Conclusion:68Ga-PSMA PET/CT could effectively detect aggressive PTEN-loss tumors.
Asunto(s)
Glicoproteínas de Membrana , Compuestos Organometálicos , Fosfohidrolasa PTEN/análisis , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Radiofármacos , Anciano , Anciano de 80 o más Años , Isótopos de Galio , Radioisótopos de Galio , Humanos , Inmunohistoquímica , Modelos Logísticos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Neoplasias de la Próstata/químicaRESUMEN
PURPOSE: Few groups have investigated the combined effects of PTEN loss and ERG expression on the outcomes of metastasis of or death from prostate cancer in surgically treated patients. We examined the association of PTEN/ERG status with lethal prostate cancer in patients treated with radical prostatectomy. MATERIALS AND METHODS: Included in analysis were 791 patients with clinically localized prostate cancer treated with radical prostatectomy at a single institution. Genetically validated immunohistochemistry assays for PTEN and ERG were performed on tissue microarrays. Multivariable Cox proportional hazard models were used to assess the association of PTEN/ERG status with lethal prostate cancer (defined as metastasis or prostate cancer specific death), adjusting for patient age, race, pathological grade and stage, and surgical margin status. RESULTS: Median followup in the cohort was 12.8 years. Of 791 cases 203 (25%) demonstrated PTEN loss and 330 of 776 (43%) were ERG positive. On multivariable analysis PTEN loss (HR 1.9, 95% CI 1.2-3.0, p=0.012) but not ERG expression (HR 0.6, 95% CI 0.4-1.1, p=0.11) was associated with an increased risk of lethal prostate cancer. The association of PTEN loss with lethal disease only remained among men with ERG negative tumors (HR 2.3, 95% CI 1.3-4.1, p=0.005) and not ERG positive tumors (HR 1.1, 95% CI 0.6-2.1, p=0.81). CONCLUSIONS: PTEN loss is associated with an increased risk of lethal prostate cancer after radical prostatectomy and this risk is most pronounced in the subgroup of patients with ERG negative tumors. This work corroborates the use of PTEN and ERG status for risk stratification in surgically treated patients.
Asunto(s)
Fosfohidrolasa PTEN/análisis , Prostatectomía , Neoplasias de la Próstata/química , Neoplasias de la Próstata/cirugía , Humanos , Masculino , Persona de Mediana Edad , Prostatectomía/métodos , Regulador Transcripcional ERG/análisis , Resultado del TratamientoRESUMEN
The activity and localization of PTEN, a tumor suppressor lipid phosphatase that converts the phospholipid PIP3 to PIP2, is governed in part by phosphorylation on a cluster of four Ser and Thr residues near the Câ terminus. Prior enzymatic characterization of the four monophosphorylated (1p) PTENs by using classical expressed protein ligation (EPL) was complicated by the inclusion of a non-native Cys at the ligation junction (aa379), which may alter the properties of the semisynthetic protein. Here, we apply subtiligase-mediated EPL to create wt 1p-PTENs. These PTENs are more autoinhibited than previously appreciated, consistent with the role of Tyr379 in driving autoinhibition. Alkaline phosphatase sensitivity analysis revealed that these autoinhibited 1p conformations are kinetically labile. In contrast to the Cys mutant 1p-PTENs, which are poorly recognized by an anti-phospho-PTEN antibody, three of the four wt 1p-PTENs are recognized by a commonly used anti-phospho-PTEN antibody.
Asunto(s)
Fosfohidrolasa PTEN/análisis , Fosfohidrolasa PTEN/metabolismo , Péptido Sintasas/metabolismo , Subtilisinas/metabolismo , Biocatálisis , Humanos , Estructura Molecular , Péptido Sintasas/química , Fosforilación , Procesamiento Proteico-Postraduccional , Subtilisinas/químicaRESUMEN
OBJECTIVE: To investigate the influences of micro ribonucleic acid (miR)-205 on renal injury in sepsis rats through the high-mobility group box 1 (HMGB1)-phosphatase and tensin homolog deleted on chromosome ten (PTEN) signaling pathway. MATERIALS AND METHODS: A rat model of sepsis-induced renal injury was established by cecal ligation and perforation. The rats were randomly divided into 3 groups, namely the Sham group, the Model group, and the miR-205 group. Hematoxylin and eosin (HE) staining was applied to examine the pathological renal morphology. The enzyme-linked immunosorbent assay (ELISA) was adopted to measure the serum levels of Caspase-3 and Bcl-2-associated X protein (Bax) in rats. Cell apoptosis rate in the renal tissues was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Finally, the protein levels of phosphorylate-HMGB1 (p-HMGB1) and p-PTEN in the renal tissues were determined using the Western blotting (WB) assay. RESULTS: Compared with those in the Sham group, the pathological morphology of the renal tissues was poor in Model group. The serum levels of Caspase-3 and Bax, the apoptosis rate, and the protein levels of p-HMGB1 and p-PTEN were remarkably enhanced in the Model group compared to the Sham group. In comparison with those in Model group, the pathological changes in renal morphology, apoptosis-related indexes, and protein levels of p-HMGB1 and p-PTEN were alleviated in the miR-205 group. CONCLUSIONS: MiR-205 agonist can improve the pathological morphology in the sepsis rats with renal injury, improve renal cell apoptosis, and inhibit the protein levels of HMGB1 and PTEN in renal tissues. MiR-205 alleviates sepsis-induced renal injury through the HMGB1-PTEN signaling pathway.
Asunto(s)
Lesión Renal Aguda/metabolismo , Proteína HMGB1/metabolismo , MicroARNs/metabolismo , Fosfohidrolasa PTEN/metabolismo , Sepsis/metabolismo , Transducción de Señal , Lesión Renal Aguda/patología , Animales , Apoptosis , Proliferación Celular , Modelos Animales de Enfermedad , Proteína HMGB1/análisis , Masculino , Fosfohidrolasa PTEN/análisis , Fosforilación , Ratas , Ratas Sprague-Dawley , Sepsis/patologíaRESUMEN
Systemic lupus erythematosus (SLE) is a devastating autoimmune disease in which hyperactive T cells play a critical role. Understanding molecular mechanisms underlying the T cell hyperactivity will lead to identification of specific therapeutic targets. Serine/arginine-rich splicing factor 1 (SRSF1) is an essential RNA-binding protein that controls posttranscriptional gene expression. We have demonstrated that SRSF1 levels are aberrantly decreased in T cells from patients with SLE and that they correlate with severe disease, yet the role of SRSF1 in T cell physiology and autoimmune disease is largely unknown. Here we show that T cell-restricted Srsf1-deficient mice develop systemic autoimmunity and lupus-nephritis. Mice exhibit increased frequencies of activated/effector T cells producing proinflammatory cytokines, and an elevated T cell activation gene signature. Mechanistically, we noted increased activity of the mechanistic target of rapamycin (mTOR) pathway and reduced expression of its repressor PTEN. The mTOR complex 1 (mTORC1) inhibitor rapamycin suppressed proinflammatory cytokine production by T cells and alleviated autoimmunity in Srsf1-deficient mice. Of direct clinical relevance, PTEN levels correlated with SRSF1 in T cells from patients with SLE, and SRSF1 overexpression rescued PTEN and suppressed mTORC1 activation and proinflammatory cytokine production. Our studies reveal the role of a previously unrecognized molecule, SRSF1, in restraining T cell activation, averting the development of autoimmune disease, and acting as a potential therapeutic target for lupus.