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OBJECTIVE: To assess the performance of apparent diffusion coefficient (ADC; values or category) alone, Prostate Imaging Reporting and Data System version 2.1 (PI-RADS v2.1) scoring alone, and the two in combination, to diagnose transition zone prostate cancers (PCas). METHODS: This retrospective study included 222 patients who underwent multiparametric magnetic resonance imaging of the prostate between May 2020 and December 2022 and who had pathologically confirmed PCa or benign prostatic hyperplasia (BPH). Prostate Imaging Reporting and Data System version 2.1 and ADC (values or category) were used in the assessment of suspicious findings identified in the transition zone. The interobserver agreements for region-of-interest measurements were calculated by intraclass correlation coefficients. Logistic regression analyses were used to determine the performance of PI-RADS v2.1 alone and in combination with ADC (values or category) to diagnose PCa. Receiver operating characteristic curve and DeLong test were used to evaluate the diagnostic performance of the quantitative parameters. RESULTS: A total of 152 patients had BPH, and 70 patients had PCa. For BPH versus PCa, the ADC values of PCa (0.64 × 10 -3 ± 0.16 × 10 -3 mm 2 /s) were significantly lower than BPH (1.06 ± 0.18 × 10 -3 mm 2 /s; P < 0.001). The PI-RADS scores for PCa (5 [interquartile range, 5-5]) were significantly higher than BPH (2 [interquartile range, 2-3]; P < 0.001). For all patients who had PI-RADS 1-5, the combined use of ADC (values or category) together with PI-RADS v2.1 did not perform significantly better than the use of PI-RADS v2.1 alone. The receiver operating characteristic of ADC category in combination with PI-RADS v2.1 score, 0.756 (95% confidence interval, 0.646-0.846), was significantly higher than that for PI-RADS 2.1 alone, 0.631 (95% confidence interval, 0.514-0.738), in PI-RADS 3-4 lesions ( P = 0.047). CONCLUSION: The ADC category can help to improve the diagnostic performance of PI-RADS v2.1 category 3-4 lesions in diagnosing PCa.
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Hiperplasia Prostática , Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos , Hiperplasia Prostática/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética/métodosRESUMEN
Macrophages in the tumor microenvironment (TME) can serve as potential targets for therapeutic intervention. The aim of this study was to investigate the molecular mechanism by which M2 macrophage-derived exosomes (M2-Ex) affect lung cancer progression through miRNA transport. The THP-1 cells were differentiated into M0 and M2 macrophages. M2-Ex were isolated and identified by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Cancer tissues and adjacent tissues of non-small-cell lung cancer (NSCLC) patients were collected. H1299 and A549 cells were co-cultured with M2-Ex. Subcutaneous xenograft mouse model was established. miR-3917 is highly expressed in lung cancer tissues and M2-Ex. Interference of miR-3917 in M2-Ex inhibits H1299 cell proliferation, migration and invasion, while overexpression of miR-3917 had the opposite effect in A549 cells. M2-Ex promote tumor growth by delivering miR-3917 in vivo. miR-3917 could target G protein-coupled receptor kinase 6 (GRK6), and interference of miR-3917 in M2-Ex inhibits H1299 cells proliferation, migration and invasion by up-regulating GRK6 level, while overexpression of miR-3917 had the opposite effect in A549 cells. M2-Ex can transfer miR-3917 into lung cancer cells and promote lung cancer progression, providing theoretical basis for the diagnosis and effective treatment of lung cancer.
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Carcinoma de Pulmón de Células no Pequeñas , Exosomas , Neoplasias Pulmonares , MicroARNs , Humanos , Ratones , Animales , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , MicroARNs/genética , Macrófagos , Exosomas/genética , Proliferación Celular , Línea Celular Tumoral , Microambiente TumoralRESUMEN
BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common type of human lung cancers, which has diverse pathological features. Although many signaling pathways and therapeutic targets have been defined to play important roles in NSCLC, limiting efficacies have been achieved. METHODS: Bioinformatics methods were used to identify differential long non-coding RNA expression in NSCLC. Real-time RT-PCR experiments were used to examine the expression pattern of lncRNA PKMYT1AR, miR-485-5p. Both in vitro and in vivo functional assays were performed to investigate the functional role of PKMYT1AR/miR-485-5p/PKMYT1 axis on regulating cell proliferation, migration and tumor growth. Dual luciferase reporter assay, fluorescent in situ hybridization (FISH), immunoblot, co-immunoprecipitation experiments were used to verify the molecular mechanism. RESULT: Here, we identify a human-specific long non-coding RNA (lncRNA, ENST00000595422), termed PKMYT1AR (PKMYT1 associated lncRNA), that is induced in NSCLC by Yin Yang 1 (YY1) factor, especially in cancerous cell lines (H358, H1975, H1299, H1650, A549 and SPC-A1) compared to that in normal human bronchial epithelium cell line (BEAS-2B). We show that PKMYT1AR high expression correlates with worse clinical outcome, and knockdown of PKMYT1AR inhibits tumor cell proliferation, migration and xenograft tumor formation abilities. Bioinformatic analysis and a luciferase assay demonstrate that PKMYT1AR directly interacts with miR-485-5p to attenuate the inhibitory role on its downstream oncogenic factor PKMYT1 (the protein kinase, membrane-associated tyrosine/threonine 1) in NSCLC. Furthermore, we uncover that miR-485-5p is downregulated in both cancerous cell lines and peripheral blood serum isolated from NSCLC patients compared to reciprocal control groups. Consistently, forced expression of miR-485-5p inhibits the proliferation and migration abilities of tumor cells. Moreover, we provide evidence showing that PKMYT1AR targeting antisense oligonucleotide (ASO) dramatically inhibit tumor growth in vivo. Mechanistic study shows that PKMYT1AR/ miR-485-5p /PKMYT1 axis promotes cancer stem cells (CSCs) maintenance in NSCLC via inhibiting ß-TrCP1 mediated ubiquitin degradation of ß-catenin proteins, which in turn causes enhanced tumorigenesis. CONCLUSIONS: Our findings reveal the critical role of PKMYT1AR/miR-485-5p /PKMYT1 axis during NSCLC progression, which could be used as novel therapeutic targets in the future.
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Carcinoma de Pulmón de Células no Pequeñas/etiología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/metabolismo , Proteínas de la Membrana/genética , Células Madre Neoplásicas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , ARN Largo no Codificante/genética , Vía de Señalización Wnt , Regiones no Traducidas 3' , Animales , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Proteínas de la Membrana/antagonistas & inhibidores , Ratones , MicroARNs , Terapia Molecular Dirigida , Oligonucleótidos Antisentido , Pronóstico , Unión Proteica , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Estabilidad Proteica , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Interferencia de ARNRESUMEN
OBJECTIVE: To explore the value of whole-brain perfusion parameters combined with multiphase computed tomography angiography (MP-CTA) in predicting the hemorrhagic transformation (HT) of ischemic stroke. METHODS: A total of 64 patients with ischemic stroke who underwent noncontrast computed tomography, computed tomography perfusion imaging, and computed tomography angiography before treatment from August 2017 to June 2019 were included retrospectively. The perfusion parameters cerebral blood volume (CBV), cerebral blood flow (CBF), time to peak (TTP), mean transit time (MTT), time to maximum (Tmax), and permeability surface (PS) were measured by postprocessing software (Advantage Workstation 4.7 (Revolution, GE Healthcare, USA)), and their ratios between the healthy and affect side relative CBV, relative CBF, relative time to peak (rTTP), relative mean transit time (rMTT), relative Tmax, and relative permeability surface (rPS) were calculated. The differences in perfusion parameters between the HT group and the non-HT group were evaluated. The collateral circulation scores and HT rates were assessed by MP-CTA. Receiver operating characteristic curves were drawn to analyze the diagnostic efficiency of valuable parameters and their correlations with HT. The rate of HT in different treatments were compared. RESULTS: The CBV values in the HT group were lower than those in the non-HT group (P < .05), while the TTP, MTT, Tmax, PS, rTTP, rMTT, and rPS values in the HT group were higher than those in the non-HT group (P < .05). PS (râ¯=â¯.63, area under curveâ¯=â¯.881) and rPS (râ¯=â¯.52, area under curveâ¯=â¯.814) were significantly correlated with HT. The combination of perfusion parameters and the MP-CTA scores can improve the diagnostic efficiency (area under curveâ¯=â¯.891). The HT rate in the group with poor collateral (64.29%) was higher than that in the group with good collateral (11.11%). CONCLUSIONS: Whole-brain perfusion parameters and MP-CTA scores have important application value in assessing the HT risk of ischemic stroke patients before treatment.
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Isquemia Encefálica/diagnóstico por imagen , Angiografía Cerebral/métodos , Circulación Cerebrovascular , Angiografía por Tomografía Computarizada , Hemorragias Intracraneales/etiología , Tomografía Computarizada Multidetector , Imagen de Perfusión/métodos , Accidente Cerebrovascular/diagnóstico por imagen , Anciano , Velocidad del Flujo Sanguíneo , Isquemia Encefálica/complicaciones , Isquemia Encefálica/fisiopatología , Isquemia Encefálica/terapia , Circulación Colateral , Femenino , Humanos , Hemorragias Intracraneales/diagnóstico por imagen , Hemorragias Intracraneales/fisiopatología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Estudios Retrospectivos , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/terapiaRESUMEN
Most clinical doctors rely on high-risk factors recommended by guidelines to decide whether to undergo adjuvant chemotherapy for stage II colon cancer. However, these high-risk factors do not include postoperative carcinoembryonic antigen (CEA). This study aims to explore the elevation of postoperative CEA as a risk factor, in addition to other high-risk factors, to guide adjuvant chemotherapy for patients with stage II colon cancer. A retrospective analysis was conducted on stage II colon cancer patients who underwent curative surgery at Yunnan Cancer Hospital and The Sixth Affiliated Hospital of Sun Yat-Sen University from April 2008 to January 2019. Patients were classified into three groups based on high-risk factors recommended by guidelines and postoperative CEA levels: low-risk with normal postoperative CEA, low-risk with elevated postoperative CEA and high-risk. COX regression analysis was used to identify independent prognostic factors affecting patients' recurrence free survival (RFS). The Kaplan-Meier method was used to create the patients' RFS curve. The restricted cubic spline (RCS) curve was used to assess the correlation between postoperative CEA and RFS on a continuous scale. Among 761 patients, there were 444 males (62.01%), with a median [IQR] age of 58.0 (18.0-88.0) years. A group of 425 high-risk patients had a 3-year RFS of 82.2% (95% CI 78.5-86.1%), while a group of 291 low-risk patients had a 3-year RFS of 89.7% (95% CI 86.1-93.5%). There was a statistically significant difference between the two groups (HR 1.83; 95% CI 1.22-2.74; P = 0.0067). Among them, the 3-year RFS of 261 low-risk patients with normal postoperative CEA was 93.6% (95% CI 90.5-96.8%), while the 3-year RFS of 30 low-risk patients with elevated postoperative CEA was 57.3% (95% CI 41.8-71.4%). There was a significant difference compared to the 3-year RFS of 425 high-risk patients (overall log-rank P < 0.0001). The multivariate analysis adjusted by the COX proportional hazards model showed that low-risk patients with elevated postoperative CEA patients (HR 14.95, 95% CI 4.51-49.63, P < 0.0001) was independently associated with a 3-year RFS. The restricted cubic spline model showed that in stage II colon cancer patients with tumor diameter > 1.955 ng/mL, the risk of postoperative recurrence increased with increasing postoperative CEA levels. Patients with elevated postoperative CEA levels have a significantly increased risk of recurrence. They should be included as high-risk factors to guide adjuvant chemotherapy for stage II colon cancer.
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Antígeno Carcinoembrionario , Neoplasias del Colon , Masculino , Humanos , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Antígeno Carcinoembrionario/análisis , Estudios Retrospectivos , Pronóstico , China , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/cirugía , Neoplasias del Colon/patología , Quimioterapia Adyuvante , Estadificación de NeoplasiasRESUMEN
The incidence of cutaneous melanoma (CM) has been increasing annually worldwide. In this study, we identify that MrgprF, a MAS related GPR family member, is decreased in cutaneous melanoma tissues and cell lines due to hypermethylation of its promoter region, and show that patients with CM expressing high levels of MrgprF exhibit an improved clinical outcome. We demonstrate that MrgprF forced expression inhibits tumor cell proliferation, migration, xenograft tumor growth, and metastasis. On the contrary, MrgprF knockdown promotes tumor cell proliferation and transformation of immortalized human keratinocyte-HaCaT cells, supporting the inhibitory role of MrgprF during tumor progression. Mechanistic studies reveal that MrgprF reduces the phosphoinositol3kinase (PI3K) complex formation between p101 and p110γ subunits, the critical step for phosphatidylinositol-(3, 4)-P2 (PIP2) conversion to phosphatidylinositol-(3, 4, 5)-P3 (PIP3), and then reduces the activation of PI3K/Akt signaling. This effect can be reversed by Akt specific agonist SC79. In addition, AMG 706, a previously documented inhibitor for endothelial cell proliferation, is identified as a potential agonist for MrgprF, and can impede tumor growth both in vitro and in vivo. Taken together, our findings suggest that MrgprF, a novel tumor suppressor in cutaneous melanoma, may be useful as a therapeutic target in the future.
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Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/genética , Melanoma/patología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositoles , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Cutáneas/genética , Melanoma Cutáneo MalignoRESUMEN
The missense variant rs13107325 (C/T, p.Ala391Thr) in SLC39A8 consistently showed robust association with schizophrenia in recent genome-wide association studies (GWASs), suggesting the potential pathogenicity of this non-synonymous risk variant. Nevertheless, how this missense variant confers schizophrenia risk remains unknown. Here we constructed a knock-in mouse model (by introducing a threonine at the 393th amino acid of mouse SLC39A8 (SLC39A8-p.393T), which corresponds to rs13107325 (p.Ala391Thr) of human SLC39A8) to explore the potential roles and biological effects of this missense variant in schizophrenia pathogenesis. We assessed multiple phenotypes and traits (associated with rs13107325) of the knock-in mice, including body and brain weight, concentrations of metal ions (including cadmium, zinc, manganese, and iron) transported by SLC39A8, blood lipids, proliferation and migration of neural stem cells (NSCs), cortical development, behaviors and cognition, transcriptome, dendritic spine density, and synaptic transmission. Many of the tested phenotypes did not show differences in SLC39A8-p.393T knock-in and wild-type mice. However, we found that zinc concentration in brain and blood of SLC39A8-p.393T knock-in mice was dysregulated compared with wild-types, validating the functionality of rs13107325. Further analysis indicated that cortical dendritic spine density of the SLC39A8-p.393T knock-in mice was significantly decreased compared with wild-types, indicating the important role of SLC39A8-p.393T in dendritic spine morphogenesis. These results indicated that SLC39A8-p.393T knock-in resulted in decreased dendritic spine density, thus mimicking the dendritic spine pathology observed in schizophrenia. Our study indicates that rs13107325 might confer schizophrenia risk by regulating zinc concentration and dendritic spine density, a featured characteristic that was frequently reported to be decreased in schizophrenia.
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Proteínas de Transporte de Catión , Esquizofrenia , Animales , Proteínas de Transporte de Catión/genética , Espinas Dendríticas/patología , Estudio de Asociación del Genoma Completo , Humanos , Ratones , Mutación Missense , Esquizofrenia/genética , Esquizofrenia/patología , ZincRESUMEN
N6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as "readers". Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.
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Adenosina/análogos & derivados , Metiltransferasas/genética , Neoplasias/genética , Procesamiento Postranscripcional del ARN/genética , Adenosina/genética , Epigénesis Genética , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Humanos , Metilación , Proteínas del Tejido Nervioso/genética , Factores de Empalme de ARN/genética , Proteínas de Unión al ARN/genéticaRESUMEN
Hypoxic environments occur normally at high altitude, or in underground burrows and in deep sea habitats. They also occur pathologically in human ischemia and in hypoxic solid tumors. Hypoxia in various cancer types and its related molecular mechanisms are associated with a poor clinical outcome. This review will discuss how hypoxia can influence two aspects of tumorigenesis, namely the direct, cell-intrinsic oncogenic effects, as well as the indirect effects on tumor progression mediated by an altered tumor microenvironment. We will also discuss recent progress in identifying the functional roles of hypoxia-related factors (HIFs), along with their regulators and downstream target genes, in cancer stem cells and therapy. Importantly, we propose, using convergent evolution schemes to identify novel biomarkers for both hypoxia adaptation and hypoxic solid tumors as an important strategy in the future.
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Hipoxia de la Célula/fisiología , Neoplasias/etiología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Hipoxia de la Célula/efectos de los fármacos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Células Madre Neoplásicas/fisiología , Microambiente Tumoral , Vía de Señalización Wnt/fisiologíaRESUMEN
PURPOSE: To evaluate the value of chest CT severity score (CT-SS) in differentiating clinical forms of coronavirus disease 2019 (COVID-19). MATERIALS AND METHODS: A total of 102 patients with COVID-19 confirmed by a positive result from real-time reverse transcription polymerase chain reaction on throat swabs who underwent chest CT (53 men and 49 women, 15-79 years old, 84 cases with mild and 18 cases with severe disease) were included in the study. The CT-SS was defined by summing up individual scores from 20 lung regions; scores of 0, 1, and 2 were respectively assigned for each region if parenchymal opacification involved 0%, less than 50%, or equal to or more than 50% of each region (theoretic range of CT-SS from 0 to 40). The clinical and laboratory data were collected, and patients were clinically subdivided according to disease severity according to the Chinese National Health Commission guidelines. RESULTS: The posterior segment of upper lobe (left, 68 of 102; right, 68 of 102), superior segment of lower lobe (left, 79 of 102; right, 79 of 102), lateral basal segment (left, 79 of 102; right, 70 of 102), and posterior basal segment of lower lobe (left, 81 of 102; right, 83 of 102) were the most frequently involved sites in COVID-19. Lung opacification mainly involved the lower lobes, in comparison with middle-upper lobes. No significant differences in distribution of the disease were seen between right and left lungs. The individual scores in each lung and the total CT-SS were higher in severe COVID-19 when compared with mild cases (P < .05). The optimal CT-SS threshold for identifying severe COVID-19 was 19.5 (area under curve = 0.892), with 83.3% sensitivity and 94% specificity. CONCLUSION: The CT-SS could be used to evaluate the severity of pulmonary involvement quickly and objectively in patients with COVID-19.© RSNA, 2020.
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Lung cancer has a high mortality rate worldwide. NonSMC condensin I complex subunit H (NCAPH) has been identified to be one of the regulatory subunits of the condensin I complex, which is essential for the correct packaging and segregation of chromosomes in eukaryotes. NCAPH is abnormally overexpressed in various types of cancer. A prosurvival member of the Bcl2 family, myeloid cell leukemia sequence 1 (Mcl1) is also frequently overexpressed in multiple cancers and is associated with poorer clinical outcomes for patients. The association of NCAPH and Mcl1 proteins with the clinical and pathological features of nonsmall cell lung cancer (NSCLC) remains to be elucidated. In the current study, the positive percentage of NCAPH in the noncancerous lung tissues was revealed to be higher compared with that in NSCLC. However, the positive percentage of Mcl1 in the noncancerous lung tissues was lower compared with NSCLC. In addition, NCAPH highexpression patients had a higher overall survival rate compared with patients exhibiting low expression, whereas the Mcl1 highexpression group had a lower survival rate. Pairwise association in 260 cases of NSCLC revealed that overexpression of the NCAPH protein was negatively associated with Mcl1 expression and vice versa. The results of multivariate Cox proportional hazard regression analysis also indicated that NCAPH and Mcl1 demonstrated potential as distinct prognostic factors that may be used in NSCLC. The expression of NCAPH and Mcl1 may be associated with, and act as distinct molecular marks for the prediction of a poor prognosis in patients with NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Proteínas de Ciclo Celular/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteínas Nucleares/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Pulmón/patología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Tasa de SupervivenciaRESUMEN
Purpose: Lung cancer is the leading cause of cancer related deaths worldwide. We have previously identified many differentially expressed genes (DEGs) from large scale pan-cancer dataset using the Cross-Value Association Analysis (CVAA) method. Here we focus on Progestin and AdipoQ Receptor 4 (PAQR4), a member of the progestin and adipoQ receptor (PAQR) family localized in the Golgi apparatus, to determine their clinical role and mechanism in the development of non-small cell lung cancer (NSCLC). Methods: The protein expression profile of PAQR4 was examined by IHC using tissue microarrays, and the effects of PAQR4 on cell proliferation, colony formation and xenograft tumor formation were tested in NSCLC cells. Real-time RT-PCR, co-immunoprecipitation (co-IP) and GST-pulldown assays were used to explore the mechanism of action of PAQR4. Results: We provided evidence showing that PAQR4 is increased in NSCLC cancer cell lines (A549, H1299, H1650, H1975, H358, GLC-82 and SPC-A1), and identified many mutations in PAQR4 in non-small cell lung cancer (NSCLC) tissues. We demonstrated that PAQR4 high expression correlates with a worse clinical outcome, and that its knockdown suppresses cell proliferation by inducing apoptosis. Importantly, overexpressed PAQR4 physically interacts with Nrf2 in NSCLC cells, blocking the interaction between Nrf2 and Keap1. Conclusion: Our results suggest that PAQR4 depletion enhances the sensitivity of cancerous cell to chemotherapy both in vitro and xenograft tumor formation in vivo, by promoting Nrf2 protein degradation through a Keap1-mediated ubiquitination process.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Resistencia a Antineoplásicos , Neoplasias Pulmonares/metabolismo , Proteínas de la Membrana/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Masculino , Ratones , Ratones Desnudos , Persona de Mediana EdadRESUMEN
Recent genome-wide association studies (GWAS) have identified multiple risk loci that show strong associations with schizophrenia. However, pinpointing the potential causal genes at the reported loci remains a major challenge. Here we identify candidate causal genes for schizophrenia using an integrative genomic approach. Sherlock integrative analysis shows that ALMS1, GLT8D1, and CSNK2B are schizophrenia risk genes, which are validated using independent brain expression quantitative trait loci (eQTL) data and integrative analysis method (SMR). Consistently, gene expression analysis in schizophrenia cases and controls further supports the potential role of these three genes in the pathogenesis of schizophrenia. Finally, we show that GLT8D1 and CSNK2B knockdown promote the proliferation and inhibit the differentiation abilities of neural stem cells, and alter morphology and synaptic transmission of neurons. These convergent lines of evidence suggest that the ALMS1, CSNK2B, and GLT8D1 genes may be involved in pathophysiology of schizophrenia.
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Quinasa de la Caseína II/genética , Predisposición Genética a la Enfermedad , Glicosiltransferasas/genética , Esquizofrenia/genética , Animales , Encéfalo/metabolismo , Quinasa de la Caseína II/metabolismo , Proteínas de Ciclo Celular , Diferenciación Celular , Proliferación Celular , Técnicas de Silenciamiento del Gen , Glicosiltransferasas/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Proteínas/genética , Proteínas/metabolismo , Sitios de Carácter Cuantitativo , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologíaRESUMEN
Lung cancer is the leading cause of cancer-related deaths worldwide, and non-small-cell lung cancer (NSCLC) accounts for about 80% of all cases, which is the major subgroup of lung cancer. G protein-coupled receptor kinase 5 (GRK5) has been demonstrated to play pivotal roles in both development and progression of several pathological conditions including cancer. Here, we found that GRK5 expression was significantly increased in 539 NSCLC cancerous tissues than that in 99 normal non-cancerous tissues by immunohistochemistry analysis; we also showed intensive higher positive staining percentage in female and adenocarcinoma (ADC) NSCLC patients than that in male and squamous cell carcinoma (SCC) patients, respectively. In addition, GRK5 high expression NSCLC patients had a worse overall survival rate than the low expression patients. We provided evidence showing that both the mRNA and protein expression levels of GRK5 were increased in NSCLC cancerous cell lines (GLC-82, SPC-A-1, H520, H838, H358, A549, and H1299) comparing with that in normal human bronchial epithelium cell line (BEAS-2B), and identified many GRK5 mutations in NSCLC cancerous tissues. In addition, we found that depletion of GRK5 inhibited NSCLC cancerous cell proliferation, migration in vitro, and xenograft tumor formation in vivo. Furthermore, GRK5 knockdown promoted cell cycle arrest at G2/M phase and induced cellular apoptosis. In summary, our data reveal an oncogenic role of GRK5 in NSCLC progression, indicating that GRK5 could be used as a new therapeutic target in future.
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Carcinoma de Pulmón de Células no Pequeñas/enzimología , Quinasa 5 del Receptor Acoplado a Proteína-G/metabolismo , Neoplasias Pulmonares/enzimología , Adulto , Anciano , Animales , Apoptosis , Carcinogénesis , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Progresión de la Enfermedad , Femenino , Quinasa 5 del Receptor Acoplado a Proteína-G/genética , Puntos de Control de la Fase G2 del Ciclo Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/fisiopatología , Puntos de Control de la Fase M del Ciclo Celular , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , OncogenesRESUMEN
In the original version of this Article, the affiliation details for Qiushuo Shen incorrectly omitted 'Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China'. This has now been corrected in both the PDF and HTML versions of the Article.
RESUMEN
Colon cancer (CC) is one of the major malignancies worldwide, whose pathogenesis is complex and requires the accumulated alteration of multiple genes and signaling pathways. Condensins are multi-protein complexes that play pivotal roles in chromosome assembly and segregation during mitosis, meiosis and even tumorigenesis. Using tissue microarrays by immunohistochemistry and hematoxylin-eosin staining, we found that non-SMC condensin I complex subunit H (NCAPH) in colon cancerous tissues was higher than that in all corresponding adjacent non-cancerous tissues. We then characterized the exact function of the NCAPH in CC. We provided evidences showing that NCAPH is highly expressed in colorectal cancer cell lines comparing with normal human colonic epithelial cells, and identified many NCAPH mutations in CC patients. We found that depletion of NCAPH inhibits CC cell proliferation, migration in vitro and xenograft tumor formation in vivo. Furthermore, NCAPH knockdown promotes cell apoptosis and cell cycle arrest at G2/M phase. Interestingly, the NCAPH high expression in tumor tissues of colon patients had a significantly better prognosis and survival rate than low-expression patients, suggesting that NCAPH high expression promotes colonic cancerous cell proliferation; on the other hand, it may also sensitize these cells responding to chemo- or radio-therapies. Collectively, these findings reveal an important role of NCAPH in CC, indicating that NCAPH could be used as a new therapeutic target in future.