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Background: Circulating metabolites, which play a crucial role in our health, have been reported to be disordered in basal cell carcinoma (BCC). Despite these findings, evidence is still lacking to determine whether these metabolites directly promote or prevent BCC's progression. Therefore, our study aims to examine the potential effects of circulating metabolites on BCC progression. Material and methods: We conducted a two-sample Mendelian randomization (MR) analysis using data from two separate genome-wide association studies (GWAS). The primary study included data for 123 blood metabolites from a GWAS with 25,000 Finnish individuals, while the secondary study had data for 249 blood metabolites from a GWAS with 114,000 UK Biobank participants.GWAS data for BCC were obtained from the UK Biobank for the primary analysis and the FinnGen consortium for the secondary analysis. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. Results: In the primary analysis, significant causal relationships were found between six metabolic traits and BCC with the inverse variance weighted (IVW) method after multiple testing [P < 4 × 10-4 (0.05/123)]. Four metabolic traits were discovered to be significantly linked with BCC in the secondary analysis, with a significance level of P < 2 × 10-4 (0.05/249). We found that all the significant traits are linked to Polyunsaturated Fatty Acids (PUFAs) and their degree of unsaturation. Conclusion: Our research has revealed a direct link between the susceptibility of BCC and Polyunsaturated Fatty Acids and their degree of unsaturation. This discovery implies screening and prevention of BCC.
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Carcinoma Basocelular , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Neoplasias Cutáneas , Humanos , Carcinoma Basocelular/sangre , Carcinoma Basocelular/genética , Carcinoma Basocelular/epidemiología , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/epidemiología , Polimorfismo de Nucleótido Simple , Femenino , Masculino , Predisposición Genética a la Enfermedad , Factores de Riesgo , Finlandia/epidemiologíaRESUMEN
Obesity induced by high-fat diet (HFD) is a multi-factorial disease including genetic, physiological, behavioral, and environmental components. Drosophila has emerged as an effective metabolic disease model. Cytidine 5'-triphosphate synthase (CTPS) is an important enzyme for the de novo synthesis of CTP, governing the cellular level of CTP and the rate of phospholipid synthesis. CTPS is known to form filamentous structures called cytoophidia, which are found in bacteria, archaea, and eukaryotes. Our study demonstrates that CTPS is crucial in regulating body weight and starvation resistance in Drosophila by functioning in the fat body. HFD-induced obesity leads to increased transcription of CTPS and elongates cytoophidia in larval adipocytes. Depleting CTPS in the fat body prevented HFD-induced obesity, including body weight gain, adipocyte expansion, and lipid accumulation, by inhibiting the PI3K-Akt-SREBP axis. Furthermore, a dominant-negative form of CTPS also prevented adipocyte expansion and downregulated lipogenic genes. These findings not only establish a functional link between CTPS and lipid homeostasis but also highlight the potential role of CTPS manipulation in the treatment of HFD-induced obesity.
The high rate of obesity has created a global health burden by leading to increased rates of chronic diseases like diabetes and cardiovascular disease. Tackling this issue is complicated as it is influenced by many factors, including genetics, behaviour and environment. To better understand the biochemical changes that underly metabolic issues in a simpler setting, scientists can study fruit flies in the laboratory. These insects share many genes with humans and have similar responses to a high-fat diet. Previous research identified an enzyme, called CTP synthase (CTPS), which is produced in large amounts by the liver and fat tissue in mammals, and the equivalent in fruit flies, known as the fat body. Multiple CTPS molecules can combine to form long strands of protein called cytoophidia, which have been seen in organisms ranging from humans to bacteria. Recent results showed that the fruit fly equivalent of CTPS drives fat cells to stick together, which is necessary to maintain and form fat tissue. However, it is not clear if altering the levels of CTPS can affect the response to a high-fat diet. To address this, Liu, Zhang, Wang et al. studied fruit flies on a high-fat diet, showing that this increased the production of CTPS. When the flies were treated to deplete levels of CTPS in the fat body, they had less body weight gain, smaller fat cells and lower amounts of fats in the body. Genetically modified flies with a version of CTPS that was unable to form cytoophidia also showed fewer signs of obesity, indicating how the enzyme might influence the response to dietary fats. These findings further implicate CTPS in the cause of obesity and help to understand its role. However, it remains to be seen if this also applies to humans. If this is the case, drugs that block the activity of CTPS could help to reduce the impact of a high-fat diet on public health.
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Dieta Alta en Grasa , Cuerpo Adiposo , Animales , Dieta Alta en Grasa/efectos adversos , Fosfatidilinositol 3-Quinasas , Obesidad/prevención & control , Peso Corporal , Drosophila , LípidosRESUMEN
Pentaxin 3 (PTX3), as a multifunctional glycoprotein, plays an important role in regulating inflammatory response, promoting tissue repair, inducing ectopic calcification and maintaining bone homeostasis. The effect of PTX3 on bone mineral density (BMD) may be affected by many factors. In PTX3 knockout mice and osteoporosis (OP) patients, the deletion of PTX3 will lead to decrease of BMD. In Korean community "Dong-gu study", it was found that plasma PTX3 was negatively correlated with BMD of femoral neck in male elderly patients. In terms of bone related cells, PTX3 plays an important role in maintaining the phenotype and function of osteoblasts (OB) in OP state;for osteoclast (OC), PTX3 in inflammatory state could stimulate nuclear factor κ receptor activator of nuclear factor-κB ligand (RANKL) production and its combination with TNF-stimulated gene 6(TSG-6) could improve activity of osteoclasts and promote bone resorption;for mesenchymal stem cells (MSCs), PTX3 could promote osteogenic differentiation of MSCs through PI3K/Akt signaling pathway. In recent years, the role of PTX3 as a new bone metabolism regulator in OP and fracture healing has been gradually concerned by scholars. In OP patients, PTX3 regulates bone mass mainly by promoting bone regeneration. In the process of fracture healing, PTX3 promotes fracture healing by coordinating bone regeneration and bone resorption to maintain bone homeostasis. In view of the above biological characteristics, PTX3 is expected to become a new target for the diagnosis and treatment of OP and other age-related bone diseases and fracture healing.
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Resorción Ósea , Curación de Fractura , Osteoporosis , Animales , Masculino , Ratones , Resorción Ósea/metabolismo , Diferenciación Celular , Curación de Fractura/genética , Osteoblastos , Osteoclastos , Osteogénesis , Osteoporosis/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/farmacologíaRESUMEN
Although most cells are mononuclear, the nucleus can exist in the form of binucleate or even multinucleate to respond to different physiological processes. The male accessory gland of Drosophila is the organ that produces semen, and its main cells are binucleate. Here we observe that CTP synthase (CTPS) forms filamentous cytoophidia in binuclear main cells, primarily located at the cell boundary. In CTPSH355A, a point mutation that destroys the formation of cytoophidia, we find that the nucleation mode of the main cells changes, including mononucleates and vertical distribution of binucleates. Although the overexpression of CTPSH355A can restore the level of CTPS protein, it will neither form cytoophidia nor eliminate the abnormal nucleation pattern. Therefore, our data indicate that there is an unexpected functional link between the formation of cytoophidia and the maintenance of binucleation in Drosophila main cells.
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Ligasas de Carbono-Nitrógeno , Drosophila , Animales , Masculino , Ligasas de Carbono-Nitrógeno/genética , Ligasas de Carbono-Nitrógeno/metabolismo , Núcleo Celular/metabolismo , Citoesqueleto/metabolismo , Drosophila/metabolismoRESUMEN
CTP synthase (CTPS) forms a filamentous structure termed the cytoophidium in all three domains of life. The female reproductive system of Drosophila is an excellent model for studying the physiological function of cytoophidia. Here, we use CTPSH355A, a point mutation that destroys the cytoophidium-forming ability of CTPS, to explore the in vivo function of cytoophidia. In CTPSH355A egg chambers, we observe the ingression and increased heterogeneity of follicle cells. In addition, we find that the cytoophidium-forming ability of CTPS, rather than the protein level, is the cause of the defects observed in CTPSH355A mutants. To sum up, our data indicate that cytoophidia play an important role in maintaining the integrity of follicle epithelium.
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Citoesqueleto , Drosophila , Animales , Femenino , Drosophila/genética , Citoesqueleto/metabolismo , Epitelio , Folículo OváricoRESUMEN
Tissue architecture determines its unique physiology and function. How these properties are intertwined has remained unclear. Here we show that the metabolic enzyme CTP synthase (CTPS) form filamentous structures termed cytoophidia along the adipocyte cortex in Drosophila adipose tissue. Loss of cytoophidia, whether due to reduced CTPS expression or a point mutation that specifically abrogates its polymerization ability, causes impaired adipocyte adhesion and defective adipose tissue architecture. Moreover, CTPS influences integrin distribution and dot-like deposition of type IV collagen (Col IV). Col IV-integrin signaling reciprocally regulates the assembly of cytoophidia in adipocytes. Our results demonstrate that a positive feedback signaling loop containing both cytoophidia and integrin adhesion complex couple tissue architecture and metabolism in Drosophila adipose tissue.
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Ligasas de Carbono-Nitrógeno , Colágeno Tipo IV , Animales , Tejido Adiposo/metabolismo , Ligasas de Carbono-Nitrógeno/química , Ligasas de Carbono-Nitrógeno/genética , Ligasas de Carbono-Nitrógeno/metabolismo , Drosophila/metabolismo , IntegrinasRESUMEN
The "undruggable" oncogene MYC supports cancer cell proliferation and survival through parallel induction of multiple anabolic processes. Here we find that inhibiting CTP synthase (CTPS) selectively decreases cell viability and induces DNA replication stress in MYC-overexpressing cells. MYC-driven rRNA synthesis caused the selective DNA replication stress upon CTPS inhibition. Combined inhibition of CTPS and ataxia telangiectasia and Rad3-related protein (ATR) is synthetically lethal in MYC-overexpressing cells, promoting cell death in vitro and decreasing tumor growth in vivo. Unexpectedly, interfering with CTPS1 but not CTPS2 is required to induce replication stress in MYC-deregulated cancer cells and consequent cell death in the presence of an ATR inhibitor. These results highlight a specific and key role of CTPS1 in MYC-driven cancer, suggesting that selectively inhibiting CTPS1 in combination with ATR could be a promising strategy to combat disease progression. SIGNIFICANCE: Inhibition of CTPS in MYC-overexpressing cells blocks pyrimidine synthesis while maintaining ribosome synthesis activity to create an anabolic imbalance that induces replication stress, providing a new approach to selectively target MYC-driven cancer. See related commentary by Chabanon and Postel-Vinay, p. 969.
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Neoplasias , Inhibidores de Proteínas Quinasas , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Humanos , Neoplasias/genéticaRESUMEN
The metabolic enzyme CTP synthase (CTPS) can form filamentous structures named cytoophidia in numerous types of cells, including follicle cells. However, the regulation of cytoophidium assembly remains elusive. The apicobasal polarity, a defining characteristic of Drosophila follicle epithelium, is established and regulated by a variety of membrane domains. Here we show that CTPS can form cytoophidia in Drosophila epithelial follicle cells. Cytoophidia localise to the basolateral side of follicle cells. If apical polarity regulators are knocked down, cytoophidia become unstable and distribute abnormally. Knockdown of basolateral polarity regulators has no significant effect on cytoophidia, even though the polarity is disturbed. Our results indicate that cytoophidia are maintained via polarised distribution on the basolateral side of Drosophila follicle epithelia, which is primarily achieved through the apical polarity regulators.
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Ligasas de Carbono-Nitrógeno/genética , Polaridad Celular/genética , Epitelio/crecimiento & desarrollo , Folículo Ovárico/crecimiento & desarrollo , Animales , Citoplasma/genética , Citoesqueleto/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Epitelio/metabolismo , Femenino , Folículo Ovárico/metabolismoRESUMEN
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway is involved in cell immunity, division and death, as well as in tumor formation. The expression of key genes in the JAK-STAT signaling pathway in different types of cancer serves different roles. However, few reports are available on the prognostic value of the genes of the JAK-STAT signaling pathway in skin cutaneous melanoma (SKCM). The potential prognostic value of gene expression in the JAK-STAT signaling pathway in patients with SKCM was analyzed in the present study using data obtained from The Cancer Genome Atlas. To predict the potential functions and mechanisms of these genes in SKCM, gene set enrichment analysis (GSEA) and bioinformatics analysis were performed. A nomogram model including gene expression level and high risk factors was used to predict the risk level of prognostic. High expression levels of STAT1, STAT3, STAT4 and STAT5B, and low expression levels of STAT6 were associated with favorable prognosis [adjusted P<0.001; hazard ratio (HR), 0.595; 95% confidence interval (CI), 0.455-0.778; adjusted P=0.018; HR, 0.725; 95% CI, 0.555-0.947; adjusted P<0.001; HR, 0.590; 95% CI, 0.450-0.773; adjusted P=0.007; HR, 0.690; 95% CI, 0.526-0.940; and adjusted P=0.026; HR, 0.737, 95% CI, 0.563-0.964, respectively]. GSEA results demonstrated that these genes were involved in cell differentiation, invasion, adhesion, migration, cycle, colony formation and mitogen-activated protein kinase signaling. The combination of genes with favorable prognosis had a better effect on the overall survival (univariate survival analysis, P<0.05). The results of the present study suggest that STAT1, STAT3, STAT4, STAT5B and STAT6 gene expression may be used as a potential prognostic biomarker of SKCM, and the combined outcomes may exhibit a stronger interaction and higher survival time for SKCM.
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Background: Hepatocellular carcinoma (HCC) has high morbidity and mortality and lacks effective biomarkers for early diagnosis and survival surveillance. Origin recognition complex (ORC), consisting of ORC1-6 isoforms, was examined to assess the potential significance of ORC isoforms for HCC prognosis. Methods: Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA) databases were used to examine differential isoform expression, stage-specific expression, calculate Pearson correlations and perform survival analysis. A human protein atlas database was utilized to evaluate the protein expression of ORCs in liver tissue. The cBioPortal database was used to assess isoform mutations and the survival significance of ORCs in HCC. Cytoscape software was employed to construct gene ontologies, metabolic pathways and gene-gene interaction networks. Results: Differential expression analysis indicated that ORC1 and ORC3-6 were highly expressed in tumor tissues in the Oncomine and GEPIA databases, while ORC2 was not. All the ORCs were showed positive and statistically significant correlations with each other (all P<0.001). ORC1-2 and ORC4-6 expressions were associated with disease stages I-IV (all P<0.05), but ORC3 was not. Survival analysis found that ORC1 and ORC4-6 expressions were associated with overall survival (OS), and ORC1-3 and ORC5-6 expression were associated with recurrence-free survival (RFS; all P<0.05). In addition, low expression of these ORC genes consistently indicated better prognosis compared with high expression. Protein expression analysis revealed that ORC1 and ORC3-6 were expressed in normal liver tissues, whereas ORC2 was not. Enrichment analysis indicated that ORCs were associated with DNA metabolic process, sequence-specific DNA binding and were involved in DNA replication, cell cycle, E2F-enabled inhibition of pre-replication complex formation and G1/S transition. Conclusions: Differentially expressed ORC1, 5 and 6 are candidate biomarkers for survival prediction and recurrence surveillance in HCC.
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Chloride channel accessory (CLCA) is a gene family that encode Ca2+ activated chloride channels, which make a substantial contribution to various diseases. The aim of the present study was to investigate the prognostic value of CLCA expression in colon cancer. In an attempt to elucidate the value of CLCA mRNA expression in the prognosis of patients with colon cancer, the gene expression data of 438 patients with colon cancer were analyzed. The source of the data was The Cancer Genome Atlas, and it was identified that high expression levels of CLCA1 and CLCA2 were associated with a favorable overall survival (OS) time in patients with colon cancer. As revealed by joint effects analysis, the co-occurrence of high expression levels of CLCA1 and CLCA2 was associated with a favorable OS time in patients with colon cancer. CLCA genes were investigated using gene set enrichment analysis. The results of the bioinformatics analysis demonstrated that high expression levels of CLCA1 and CLCA2 were associated with the prognosis of colon cancer. These findings suggest that CLCA1 and CLCA2 are potential prognostic biomarkers for patients with colon cancer. Furthermore, combining CLCA1 and CLCA2 can enhance the sensitivity of the prediction of the OS time of patients with colon cancer.
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Hepatocellular carcinoma (HCC) is one of the leading causes of tumorrelated mortalities worldwide. Long noncoding RNAs have been reported to be associated with tumor initiation, progression and prognosis. The present study aimed to explore the association between long noncoding RNA LINC00668 and its coexpression correlated proteincoding genes (PCGs) in HCC. Data of 370 HCC patients from The Cancer Genome Atlas database were used for analysis. LINC00668 and its top 10 PCGs were selected to determine their diagnostic and prognostic value. Molecular mechanisms were explored to identify metabolic processes that LINC00668 and its PCGs are involved in. Prognosisrelated clinical factors and PCGs were used to construct a nomogram for predicting prognosis in HCC. A Connectivity Map was constructed to identify candidate target drugs for HCC. The top 10 PCGs identified were: Pyrimidineregic receptor P2Y4 (P2RY4), signal peptidase complex subunit 2 (SPCS2), family with sequence similarity 86 member C1 (FAM86C1), tudor domain containing 5 (TDRD5), ferritin light chain (FTL), stratifin (SFN), nucleolar complex associated 2 homolog (NOC2L), peroxiredoxin 1 (PRDX1), cancer/testis antigen 2 CTAG2 and leucine zipper and CTNNBIP1 domain containing (LZIC). FAM86C1, CTAG2 and SFN had significant diagnostic value for HCC (total area under the curve ≥0.7, P≤0.05); LINC00668, FAM86C1, TDRD5, FTL and SFN were of significant prognostic value for HCC (all P≤0.05). Investigation into the molecular mechanism indicated that LINC00668 affects cell division, cell cycle, mitotic nuclear division, and drug metabolism cytochrome P450 (all P≤0.05). The Connectivity Map identified seven candidate target drugs for the treatment of HCC, which were: Indolylheptylamine, mimosine, disopyramide, lidocaine, NU1025, bumetanide, and DQNLAOWBTJPFKLPKZXCIMASAN (all P≤0.05). Our findings indicated that LINC00668 may function as an oncogene and its overexpression indicates poor prognosis of HCC. FAM86C1, CTAG2 and SFN are of diagnostic significance, while FAM86C1, TDRD5, FTL and SFN are of prognostic significance for HCC.
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Carcinoma Hepatocelular/genética , Redes Reguladoras de Genes , Estudio de Asociación del Genoma Completo/métodos , Neoplasias Hepáticas/genética , ARN Largo no Codificante/genética , Regulación hacia Arriba , Ciclo Celular , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Pronóstico , Mapas de Interacción de Proteínas , Análisis de SupervivenciaRESUMEN
Background: The functional significance of the proteasome activator subunit (PSME) gene family in the pathogenesis of skin cutaneous melanoma (SKCM) remains to be elucidated. Materials and methods: Clinical data for patients with SKCM, including expression levels of PSME genes, were extracted from TCGA. GO term and KEGG pathway enrichment analyses were performed. Correlations between the expression levels of PSME genes in SKCM were evaluated with the Pearson correlation coefficient. Functional and enrichment analyses were conducted using DAVID. Univariate and multivariate survival analyses adjusted by Cox regression were used to construct a prognostic signature. The mechanisms underlying the association between PSME gene expression and overall survival (OS) were explored with gene set enrichment analysis. Joint-effects survival analysis was performed to evaluate the clinical value of the prognostic signature. Results: The median expression levels of PSME1, PSME2 and PSME3 were significantly higher in SKCM than in normal skin. PSME1, PSME2, and PSME3 were significantly enriched in several biological processes and pathways including cell adhesion, adherens junction organization, regulation of autophagy, cellular protein localization, the cell cycle, apoptosis, and the Wnt and NF-κB pathways. High expression levels of PSME1 and PSME2 combined with a low expression level of PSME3 was associated with favorable OS. Conclusion: Knowledge of the expression levels of the PSME gene family could provide a sensitive strategy for predicting prognosis in SKCM.
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Objective: MicroRNAs (miRNAs) have been explored in malignancies. We investigated the functions of clustered miRNAs hsa-miR-221/222-3p in hepatocellular carcinoma (HCC). Methods: Human miRNA tissue atlas website was determined expression levels in liver tissue. Four databases, TarBase, miRTarBase, miRecords and miRPathDB, were found experimentally validated target genes of clustered miRNAs. TargetScanHuman was predicted target genes. The STRING website was depicted protein-protein interaction (PPI) networks. The OncoLnc website analyzed prognostic values for hsa-miR-221/222-3p and their target genes. The MCODE plugin calculated modules of PPI networks. Receiver operating characteristic (ROC) curves were predicted 1, 3, and 5 years prognostic values. Results: Expression of clustered miRNAs was high in liver tissues. A total of 1577 target genes were identified. Enrichment analysis showed that target genes were enriched mainly in cancer, Wnt signaling and ErbB signaling pathways. Two modules were calculated using PPI networks. Has-miR-221-3p was not associated with prognosis (P = 0.401). Has-miR-222-3p and target genes ESR1, TMED7, CBFB, ETS2, UBE2J1 and UBE2N of the clustered miRNAs were associated with HCC survival (all P < 0.05). Has-miR-222-3p, CBFB, and UBE2N showed good performance of ROC in prognosis prediction at 1, 3, and 5 years (all area under curves > 0.600). Conclusion: Has-miR-222-3p and target genes, especially CBFB, UBE2N, may serve as prognostic predictors for HCC.
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BACKGROUND: Hepatocellular carcinoma (HCC) is among the most common and lethal malignancies worldwide. Apolipoproteins (APOs) have been reported increasingly for their relationships with tumors. We aim at exploring the potential relationships of apolipoprotein A (APOA) and apolipoprotein C (APOC) family members with HCC. METHODS: A data set, containing 212 hepatitis B virus-related HCC patients, was used for analysis. The diagnostic and prognostic ability of APOA and APOC family genes was figured out. Risk score models and nomograms were developed for the HCC prognosis prediction. Moreover, molecular mechanism exploration were identified biological processes and metabolic pathways of these genes involved in. Validation analysis was carried out using online website. RESULTS: APOA1, APOC1, APOC3, and APOC4 showed robust diagnosis significance (all P < 0.05). APOA4, APOC3, and APOC4 were associated with the overall survival (OS) while APOA4 and APOC4 were linked to recurrence-free survival (RFS, all P ≤ 0.05). Risk score models and nomograms had the advantage of predicting OS and RFS for HCC. Molecular mechanism exploration indicated that these genes were involved in the steroid metabolic process, the PPAR signaling pathway, and fatty acid metabolism. Besides that, validation analysis revealed that APOC1 and APOC4 had an association with OS; and APOC3 was associated with OS and RFS (all P ≤ 0.05). CONCLUSIONS: APOA1, APOC1, APOC3, and APOC4 are likely to be potential diagnostic biomarkers and APOC3 and APOC4 are likely to be potential prognostic biomarkers for hepatitis B virus-related HCC. They may be involved in the steroid metabolic process, PPAR signaling pathway, and fatty acid metabolism.
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Apolipoproteínas A/genética , Apolipoproteínas C/genética , Carcinoma Hepatocelular/genética , Regulación Neoplásica de la Expresión Génica , Hepatitis/complicaciones , Neoplasias Hepáticas/genética , ARN Mensajero/genética , Apolipoproteínas A/metabolismo , Apolipoproteínas C/metabolismo , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Ontología de Genes , Redes Reguladoras de Genes , Hepatitis/virología , Virus de la Hepatitis B/fisiología , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Nomogramas , Pronóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/metabolismoRESUMEN
BACKGROUND: Colon adenocarcinoma (COAD) is ranked as the third most commonly diagnosed cancer in both women and men, and it is the most frequently occurring malignant tumor. Dynactin is a protein compound based on multiple subunits, including dynactin 1-6 (DCTN1-6), in most categories of cytoplasmic dynein performance in eukaryotes. Nevertheless, correlations between the DCTN family and the prognosis and diagnosis of COAD remain unidentified. METHODS: Statistics for DCTN mRNA expression in patients with COAD were acquired from The Cancer Genome Atlas. Kaplan-Meier analyses and a Cox regression model were applied to determine overall survival, with computation of HRs and 95% CIs. Several online data portals were used to assess the biological process, and pathway examination was performed using the Kyoto Encyclopedia of Genes and Genomes to predict the biological functionality of DCTN genes. RESULTS: We found that high expression of DCTN4 was linked with satisfactory results for overall survival (P=0.042, HR=0.650, 95% CI 0.429-0.985). The expression of DCTN1, DATN2, and DCTN4 was closely correlated with the frequency of colon tumors (P<0.001, area under the curve [AUC]=0.8811, 95% CI 0.8311-0.9312; P<0.001, AUC=0.870, 96% CI 0.833-0.9071; and P=0.0051, AUC=0.6317, 95% CI 0.5725-0.6908, respectively). In the enrichment examination, the level of gene expression was related to the cell cycle, cell apoptosis, and the cell metastasis pathway. CONCLUSION: The expression levels of DCTN1, DCTN2, and DCTN4 could allow differentiation between cancer-bearing tissues and paracancerous tissue. These genes can be applied as biomarkers to predict the prognosis and diagnosis of COAD.
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BACKGROUND Dynactin (DCTN) is a multi-subunit protein encoded by DCTN genes for 6 subunits. In different diseases the DCTN genes may have different roles; therefore, we investigated the prognostic potential of DCTN mRNA expression in cutaneous melanoma (CM). MATERIAL AND METHODS Data for DCTN mRNA expression in CM patients were obtained from the OncoLnc database, which contains updated gene expression data for 459 CM patients based on the Cancer Genome Atlas. Kaplan-Meier analysis and a Cox regression model were used to determine overall survival (OS) with calculation of hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS The multivariate survival analysis showed that individually low expression of DCTN1, DCTN2, and DCTN5 and high expression of DCTN6 were associated with favorable OS (adjusted P=0.008, HR=0.676, 95% CI=0.506-0.903; adjusted P=0.004, HR=0.648, 95% CI=0.485-0.867; adjusted P=0.011, HR=0.686, 95% CI=0.514-0.916; and adjusted P=0.018, HR=0.706, 95% CI=0.530-0.942, respectively). In a joint-effects analysis, combinations of low expression of DCTN1, DCTN2, and DCTN5 and high expression of DCTN6 were found to be more highly correlated with favorable OS (all P<0.05). CONCLUSIONS Our findings suggest that downregulated DCTN1, DCTN2, and DCTN5 and upregulated DCTN6 mRNA expression in CM are associated with favorable prognosis and may represent potential prognostic biomarkers. Moreover, use of the 4 genes in combination can improve the sensitivity for predicting OS in CM patients.
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Complejo Dinactina/genética , Melanoma/genética , Neoplasias Cutáneas/genética , Biomarcadores de Tumor/genética , Bases de Datos de Ácidos Nucleicos , Humanos , Estimación de Kaplan-Meier , Pronóstico , Modelos de Riesgos Proporcionales , ARN Mensajero/genética , Análisis de Supervivencia , Transcriptoma/genética , Melanoma Cutáneo MalignoRESUMEN
The purpose of the present study was to assess if guanylate-binding protein (GBP) mRNAs could be prognostic biomarkers for patients with skin cutaneous melanoma (SKCM). The prognostic value of GBP mRNA expression in patients with SKCM was investigated by analyzing gene expression data in 459 SKCM patients. The data were extracted from the OncoLnc database of The Cancer Genome Atlas. A high expression of GBP1, GBP2, GBP3, GBP4 and GBP5 were correlated with favorable overall survival (OS) in the SKCM patients followed for over 30 years. In addition, a high expression of GBP6 mRNA was not correlated with OS in the SKCM patients. A joint effects analysis showed that the co-incidence of the high expression of GBP1-5 was correlated with favorable overall survival in SKCM patients. Our findings suggest that GBP1-5 mRNAs in SKCM are associated with favorable prognosis and may be potential prognostic biomarkers. The combination of GBP1-5 could improve the sensitivity for predicting OS in SKCM patients.