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1.
Pathol Res Pract ; 216(2): 152785, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31889588

RESUMO

The relationship between integrin beta 4 (ITGB4) expression and laryngeal squamous cell carcinoma (LSCC) remains unclarified. The object of the present study was to explore the clinical significance and potential molecular mechanism of ITGB4 in LSCC. The protein level of ITGB4 was significantly higher in 46 LSCC patients than in 26 non-LSCC tissues detected by in-house immunohistochemistry. Consistently, ITGB4 mRNA level was also greatly upregulated based on microarray and RNA-seq data (standard mean difference, SMD = 1.62, 95 % CI: 1.23-2.00). And the area under curves (AUC) of summary receiver operator characteristic (SROC) was 0.87 (95 % CI: 0.84-0.90) based on 172 cases of LSCC and 59 cases of non-cancerous controls. Ninety genes were intersected by the ITGB4 related genes and LSCC differential expressed genes (DEGs) from all available microarray and RNA-seq datasets. Based on Gene Ontology (GO) analysis, the top terms of biological process (BP), cellular component (CC) and molecular function (MF) for the 90 ITGB4 related DEGs were extracellular matrix organization, basement membrane and extracellular matrix structural constituent, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that ITGB4 related DEGs mainly participated in the pathways of ECM-receptor interaction, Focal adhesion and Small cell lung cancer. Moreover, the Protein-Protein Interaction (PPI) network indicated that ITGA3, ITGA5, ITGB4, MET, LAMA3, and COL4A1 might be the core genes of LSCC development related to ITGB4. In conclusion, high ITGB4 expression may lead to the occurrence and development of LSCC via various signaling pathways.

2.
J Cell Physiol ; 235(4): 3823-3834, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31612488

RESUMO

Neuroblastoma (NBL) is the most frequently encountered extracranial solid neoplasm and impacts significantly on the survival of patients, especially in cases of advanced tumor stage or relapse. A long noncoding RNA (lncRNA) signature to predict the survival of patients with NBL is proposed in this paper. Differentially expressed lncRNA (DElncRNA) was selected using the Limma plus Voom package in R based on the RNA-sequencing data downloaded from the Therapeutically Applicable Research To Generate Effective Treatments database and Genotype-Tissue Expression database. Univariate cox regression analysis, least absolute shrinkage and selection operator regression analysis, and multivariate cox regression analysis were conducted to identify candidate DElncRNAs for the risk signature. Consequently, 10 DElncRNAs were designated as candidate DElncRNAs for the risk signature. Time-dependent receiver operating characteristic curves and Kapan-Meier survival curves confirmed the efficacy of the risk signature in predicting the survival of patients with NBL (area under the curve = 0.941; p ≤ .001). One of the DElncRNA constituent subparts (LINC01010) was significantly associated with the survival outcome of patients with NBL in GSE62564 (p = .004). Thus, a risk signature comprising 10 DElncRNAs was identified as effective for individual risk stratification and the survival prediction outcomes of patients with NBL.

3.
Onco Targets Ther ; 12: 9827-9848, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819482

RESUMO

Introduction: MIR22HG has a reported involvement in the tumorigenesis of a variety of cancers, including hepatocellular carcinoma (HCC). However, the exact molecular mechanism of MIR22HG in HCC has not been clarified. Methods: In the present study, we integrated data from in-house RT-qPCR, RNA-sequencing, microarray, and literature studies to conduct a comprehensive evaluation of the clinico-pathological and prognostic significance of MIR22HG in an extremely large group of HCC samples. We also explored the potential mechanism of MIR22HG in HCC by analyzing the alteration profiles of MIR22HG in HCC to predict transcription factors (TFs) that may interact with MIR22HG and to annotate the biological functions of genes co-expressed with MIR22HG. MIR22HG expression was also compared in HCC nude mice xenografts before and after a treatment with nitidine chloride. Results: We found that MIR22HG was downregulated in HCC and that this downregulation correlated with the malignant phenotype of HCC. Comprehensive analysis of the prognostic impact of MIR22HG in HCC revealed a beneficial effect of MIR22HG on the survival outcome of HCC patients. Seven cases of MIR22HG deep deletion occurred in 360 of the cancer genome atlas (TCGA) provisional HCC samples. A total of 22 MIR22HG-TF-mRNA triplets in HCC were predicted by the lncRNAmap. Co-expressed genes of MIR22HG, identified by weighted correlation network analysis (WGCNA), mainly participated in the pathways involving osteoclast differentiation, chemokine signaling pathways, and hematopoietic cell lineage. In vivo experiments demonstrated that nitidine chloride could stimulate MIR22HG expression in HCC xenografts. Conclusion: In summary, MIR22HG may play a tumor-suppressive role in HCC by coordinating with predicted TFs and co-expressed genes, such as NLRP3, CSF1R, SIGLEC10, and ZEB2, or by being controlled by nitidine chloride.

4.
World J Clin Cases ; 7(21): 3671-3682, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31750352

RESUMO

BACKGROUND: Primitive neuroectodermal tumors are rare, highly malignant small round cell tumors belonging to the Ewing sarcoma family. The purpose of this article is to present clinical manifestation, histology, treatment, and prognosis of two primitive neuroectodermal tumors (PNETs) in extremely rare anatomic locations, the abdominal wall and vulva. CASE SUMMARY: Case 1 was a 66-month-old girl with lesions on the abdominal wall; tumor size was about 3.4 cm × 6.1 cm × 2 cm. The patient underwent radical resection of the tumor. After the operation, an alternating vincristine, doxorubicin, and cyclophosphamide/ifosfamide and etoposide (IE) regimen was given for eight cycles, and the patient survived for 66 mo without progression. Case 2 was a 40-month-old girl, with a vulvar lesion; tumor size was about 3.3 cm × 5 cm × 2.5 cm. The tumor was partially resected by surgery. The family left treatment after two cycles of vincristine, pirarubicin, and cyclophosphamide/IE chemotherapy, and the patient died at home six months after surgery. CONCLUSION: PNET is a rare, fast-growing, highly malignant tumor that requires histologic and molecular analyses for exact diagnosis, and multimodal treatment is required to achieve a good prognosis.

5.
Cancer Med ; 8(18): 7623-7636, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31674730

RESUMO

BACKGROUND: Increasing evidence has validated the crucial role of alternative splicing (AS) in tumors. However, comprehensive investigations on the entirety of AS and their clinical value in glioblastoma (GBM) are lacking. METHODS: The AS profiles and clinical survival data related to GBM were obtained from The Cancer Genome Atlas database. Univariate and multivariate Cox regression analyses were performed to identify survival-associated AS events. A risk score was calculated, and prognostic signatures were constructed using seven different types of independent prognostic AS events, respectively. The Kaplan-Meier estimator was used to display the survival of GBM patients. The receiver operating characteristic curve was applied to compare the predictive efficacy of each prognostic signature. Enrichment analysis and protein interactive networks were conducted using the gene symbols of the AS events to investigate important processes in GBM. A splicing network between splicing factors and AS events was constructed to display the potential regulatory mechanism in GBM. RESULTS: A total of 2355 survival-associated AS events were identified. The splicing prognostic model revealed that patients in the high-risk group have worse survival rates than those in the low-risk group. The predictive efficacy of each prognostic model showed satisfactory performance; among these, the Alternate Terminator (AT) model showed the best performance at an area under the curve (AUC) of 0.906. Enrichment analysis uncovered that autophagy was the most enriched process of prognostic AS gene symbols in GBM. The protein network revealed that UBC, VHL, KCTD7, FBXL19, RNF7, and UBE2N were the core genes in GBM. The splicing network showed complex regulatory correlations, among which ELAVL2 and SYNE1_AT_78181 were the most correlated (r = -.506). CONCLUSIONS: Applying the prognostic signatures constructed by independent AS events shows promise for predicting the survival of GBM patients. A splicing regulatory network might be the potential splicing mechanism in GBM.

6.
J Cancer ; 10(22): 5355-5370, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632480

RESUMO

Objective: To enquire into the clinical significance and potential molecular mechanism of microRNA (miRNA)-196b-5p in hepatocellular carcinoma (HCC). Methods: Quantitative reverse transcription and polymerase chain reaction (qRT-PCR) were utilized to examine miR-196b-5p expression level in 67 HCC paraffin embedded tissues and corresponding adjacent tissues. Correlations of miR-196b-5p expression level with clinicopathological characteristics were analyzed in our study. The expression level and clinical significance of miR-196b-5p in HCC were also evaluated in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. We made predictions of the target genes of miR-196b-5p by twelve online software and then selected genes predicted by at least 5 software. Subsequently, in order to obtain the potential target genes of miR-196b-5p, we overlapped the predicted target genes and down-regulated mRNAs in HCC based on TCGA database. Then, we performed the Gene Ontology (GO) and the Disease Ontology (DO) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Protein-Protein Interaction (PPI) network construction of those miR-196b-5p potential target genes. Results: Higher expression level of miR-196b-5p was seen in HCC tissues than in the corresponding adjacent tissues based on qRT-PCR (P = 0.0007). The expression level of miR-196b-5p was linked with tumor size (P = 0.03), tumor node (P = 0.024), vascular invasion (P = 0.029) and capsular invasion (P = 0.026) in HCC patients. Comprehensive meta-analysis of miR-196b-5p expression based on TCGA, GEO and qRT-PCR verified that higher expression level of miR-196b-5p was observed in HCC tissues than in normal control liver tissues (SMD = 0.56, 95%CI: 0.39-0.72, P heterogeneity = 0.275, I2 = 18.3%). GO annotation revealed that the top terms in biological process, cellular component and molecular function were single-organism catabolic process, neuronal cell body and transmembrane receptor protein kinase activity, respectively. The most relevant disease in DO annotation was arteriosclerosis. The tryptophan metabolism pathway ranked first in KEGG pathway enrichment analysis. The PPI network showed that IGF1, FOXO1, AR and FOS were mostly likely to become the core genes of miR-196b-5p potential target genes, which however required further experiments for validation. Conclusion: The miR-196b-5p was observed to show higher expression in HCC tissues than in normal control liver tissues. Moreover, the miR-196b-5p expression level had correlations with the clinicopathological parameters such as vascular invasion of HCC, but the molecular mechanisms of miR-196b-5p in HCC still need further elucidation and verification.

7.
Cell Death Dis ; 10(9): 658, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506425

RESUMO

Nitidine chloride (NC) has been demonstrated to have an anticancer effect in hepatocellular carcinoma (HCC). However, the mechanism of action of NC against HCC remains largely unclear. In this study, three pairs of NC-treated and NC-untreated HCC xenograft tumour tissues were collected for circRNA sequencing analysis. In total, 297 circRNAs were differently expressed between the two groups, with 188 upregulated and 109 downregulated, among which hsa_circ_0088364 and hsa_circ_0090049 were validated by real-time quantitative polymerase chain reaction. The in vitro experiments showed that the two circRNAs inhibited the malignant biological behaviour of HCC, suggesting that they may play important roles in the development of HCC. To elucidate whether the two circRNAs function as "miRNA sponges" in HCC, we identified circRNA-miRNA and miRNA-mRNA interactions by using the CircInteractome and miRwalk, respectively. Subsequently, 857 miRNA-associated differently expressed genes in HCC were selected for weighted gene co-expression network analysis. Module Eigengene turquoise with 423 genes was found to be significantly related to the survival time, pathology grade and TNM stage of HCC patients. Gene functional enrichment analysis showed that the 423 genes mainly functioned in DNA replication- and cell cycle-related biological processes and signalling cascades. Eighteen hubgenes (SMARCD1, CBX1, HCFC1, RBM12B, RCC2, NUP205, ECT2, PRIM2, RBM28, COPS7B, PRRC2A, GPR107, ANKRD52, TUBA1B, ATXN7L3, FUS, MCM8 and RACGAP1) associated with clinical outcomes of HCC patients were then identified. These findings showed that the crosstalk between hsa_circ_0088364 and hsa_circ_0090049 and their competing mRNAs may play important roles in HCC, providing interesting clues into the potential of circRNAs as therapeutic targets of NC in HCC.

8.
Am J Transl Res ; 11(7): 4010-4028, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396315

RESUMO

Alternative splicing (AS) has been widely reported to play an important role in cancers, including esophageal carcinoma (ESCA). However, no study has comprehensively investigated the clinical use of combination of prognostic AS events and clinicopathological parameters. Therefore, we collected 165 ESCA patients including 83 esophageal adenocarcinoma (EAC) and 82 esophageal squamous cell carcinoma (ESCC) patients from The Cancer Genome Atlas to explore the survival rate associated with seven types of AS events. Prognostic predictors for the clinical outcomes of ESCA patients were built. Predictive prognosis models of the alternative acceptor site in ESCA (area under the curve [AUC] = 0.83), alternative donor site in EAC (AUC = 0.99), and alternative terminator site in ESCC (AUC = 0.974) showed the best predictive efficacy. A novel combined prognostic model of AS events and clinicopathological parameters in ESCA was also constructed. Combined prognostic models of ESCA all showed better predictive efficacy than independent AS models or clinicopathological parameters model. Through constructing splicing regulatory network, the expression of AS factor was found to be negatively correlated with the most favorable AS events. Moreover, gene amplification, mutation, and copy number variation of AS genes were commonly observed, which may indicate the molecular mechanism of how the AS events influence survival. Conclusively, the constructed prognostic models based on AS events, especially the combined prognostic models of AS signatures and clinicopathological parameters could be used to predict the outcome of ESCA patients. Moreover, the splicing regulatory network and genomic alteration in ESCA could be used for illuminating the potential molecular mechanism.

9.
Int J Oncol ; 55(2): 425-438, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268164

RESUMO

Alternative splicing in tumor cells may be used as a molecular marker for the differential diagnosis of certain tumor types and assessment of prognosis. The aim of the present study was to investigate the associations among alternative splicing events, splicing factors, and the survival of patients with hepatocellular carcinoma (HCC). The alternative splicing event profiles of 371 patients with HCC were downloaded from The Cancer Genome Atlas (TCGA) SpliceSeq data, and the percent­splice­in value for each splicing event was calculated. The association between alternative splicing events and overall survival was evaluated. The most significant prognosis­related splicing events were used to build up a prognostic index (PI). A total of 3,082 survival­associated alternative splicing events were detected in HCC. The final PI based on all of the most significant candidate alternative splicing events exhibited better performance in distinguishing good or poor survival in patients compared to the PI based on a single type of splicing event. Receiver operating characteristic curves confirmed the high efficiency of the PI in predicting the survival of HCC patients, with an area under the curve of 0.914. The overexpression of 32 prognosis­related splicing factor genes could also predict poor prognosis in patients with HCC. In conclusion, the constructed computational prognostic model based on HCC­specific alternative splicing events may be used as a molecular marker for the prognosis of HCC.


Assuntos
Processamento Alternativo , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/secundário , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , RNA Mensageiro/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Curva ROC , Taxa de Sobrevida
10.
Cancer Cell Int ; 19: 167, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31285693

RESUMO

Background/aims: Studies have shown that miR-146a-5p was differentially expressed in diverse cancers, but the associations between miR-146a-5p expression and prognosis across multiple types of cancer as well its potential targets and downstream pathways have not been comprehensively analyzed. In this study, we performed the first meta-analysis of the prognostic value of miR-146a-5p expression in diverse malignancies and explored prospective targets of miR-146a-5p and related signaling pathways. Methods: A thorough search for articles related to miR-146a-5p was performed, and RNA-seq data from The Cancer Genome Atlas (TCGA) and microarray data from gene expression omnibus profiles were used to collect information about the prognostic value of miR-146a-5p. A comprehensive meta-analysis was conducted. Twelve platforms in miRWalk 2.0 were applied to predict targets of miR-146a-5p. TCGA RNA-seq data were used to validate the inverse relationships between miR-146a-5p and its likely targets. Subsequently, gene ontology and pathway analyses were conducted using Funrich version 3.1.3. Potential protein-protein interaction (PPI) networks were constructed. Potential target genes of miR-146a-5p in lung cancer were validated by RT-qPCR. Results: We included 10 articles in the meta-analysis. In a pooled analysis, the high miR-146a-5p expression group showed a better overall survival in solid cancers, particularly in reproductive system cancers and digestive system cancers. A total of 120 predicted target genes were included in a bioinformatics analysis. Five pathways involving phospholipase C (PLC) and aquaporins (AQPs) were the most significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways. Moreover, the PPI network displayed the related signaling pathways and interactions among proteins. AQP1 and FYN were validated by RT-qPCR to be potential targets of miR-146a-5p in lung cancer. Conclusion: There is a close link between high miR-146a-5p expression and better overall survival in 21 types of solid cancer, especially in reproductive system and digestive system cancers. Furthermore, miR-146a-5p could inhibit diverse malignancies by modulating pathways linked to PLC or AQPs. In summary, miR-146a-5p is a potential prognostic biomarker and therapeutic target for various cancers.

11.
Cancer Manag Res ; 11: 4825-4837, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213904

RESUMO

Background: MicroRNAs (miRNAs) could modulate gene expression at the posttranscriptional level by promoting mRNA degradation or blocking mRNA translation, thus affecting the occurrence and development of cancer. Methods: In this work, qRT-PCR was conducted to detect the expression of miR-193a-3p and CCND1. The ability of cell proliferation was evaluated via CCK-8 assay. Cell apoptosis and cell cycle distribution were detected by flow cytometry. Bioinformatic techniques were employed to research the regulatory relationship between miR-193a-3p and target genes. The relationship between miR-193a-3p and CCND1 was verified via dual-luciferase reporter assays. Results: MiR-193a-3p expression in pancreatic ductal adenocarcinoma (PDAC) tissue was significantly lower than in non-cancerous tissue. After overexpressing miR-193a-3p in PDAC cells, their multiplication ability was significantly inhibited, apoptosis was accelerated, and the cell cycle was blocked in the G1 and G2/M phases. CCND1 was confirmed to have a targeted relationship with miR-193a-3p. Moreover, CCND1 expression was significantly lower in PDAC cells with an overexpression of miR-193a-3p. Conclusions: MiR-193a-3p targeted CCND1 to suppress tumor growth in PDAC cells. MiR-193a-3p may function as a tumor inhibitor in PDAC development, which could offer a promising therapeutic and prognostic strategy for PDAC treatment.

12.
Oncol Rep ; 42(1): 151-175, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31059074

RESUMO

Breast cancer (BC) has a complex etiology and pathogenesis, and is the most common malignant tumor type in females, in USA in 2018, yet its relevant molecular mechanisms remain largely unknown. The collagen type V α­1 chain (COL5A1) gene is differentially expressed in renal and ovarian cancer. Using bioinformatics methods, COL5A1 was determined to also be a significant gene in BC, but its association with BC has not been sufficiently reported. COL5A1 microarray and relevant clinical data were collected from the Gene Expression Omnibus, The Cancer Genome Atlas and other databases to summarize COL5A1 expression in BC and its subtypes at the mRNA and protein levels. All associated information was comprehensively analyzed by various software. The clinical significance of the mutation was obtained via the cBioPortal. Furthermore, Gene Ontology functional annotation and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were also performed to investigate the mechanism of COL5A1 in BC. Immunohistochemistry was also conducted to detect and confirm COL5A1 expression. It was determined that COL5A1 was highly expressed in BC tissues, compared with normal tissues at the mRNA level [standard mean difference, 0.84; 95% confidence interval (CI), 0.60­1.07; P=0.108]. The area under the summary receiver operator characteristic curve for COL5A1 was 0.87 (95% CI, 0.84­0.90). COL5A1 expression was altered in 32/817 (4%) sequenced samples. KEGG analysis confirmed the most notable pathways, including focal adhesion, extracellular matrix­receptor interaction and regulation of the actin cytoskeleton. Immunohistochemical detection was used to verify the expression of COL5A1 in 136 selected cases of invasive BC tissues and 55 cases of adjacent normal tissues, while the rate of high expression of COL5A1 in BC was up to 90.4%. These results indicated that COL5A1 is highly expressed at the mRNA and protein levels in BC, and the prognosis of patients with BC with high COL5A1 expression may be reduced; therefore, COL5A1 may be used independently or combined with other detection factors in BC diagnosis.


Assuntos
Neoplasias da Mama/metabolismo , Colágeno Tipo V/genética , Colágeno Tipo V/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Análise de Sequência de RNA/métodos , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Mapas de Interação de Proteínas , Curva ROC , Análise de Sobrevida , Regulação para Cima
13.
Pathol Res Pract ; 215(7): 152424, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31103408

RESUMO

BACKGROUND AND AIM: Extensive research has revealed that microRNAs (miRNAs) play a principle role in cancer, and miRNAs associated with specific cancers have also been identified. The role of microRNA (miR)-302b-5p, which is one of the miRNAs reported in association with cancer, in hepatocellular carcinoma (HCC) is still unclear. Thus, the present study aimed to reveal the expression and potential molecule mechanism of miR-302b-5p in HCC. METHODS: An extensive meta-analysis of data from real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR), Gene Expression Omnibus and ArrayExpress microarrays was used to determine the expression of miR-302b-5p in HCC tissue samples and non-cancerous liver tissue samples. The sensitivity and specificity of miR-302b-5p as an indicator of HCC was estimated by plotting the receiver operating characteristic (ROC) and summarized ROC (sROC). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were employed to unravel the molecular mechanisms and biological functions of miR-302b-5p in HCC. Further, the putative target genes of miR-302b-5p were harvested based on the predicted genes and differentially expressed genes in HCC. Finally, the protein-protein interaction (PPI) network was built to determine the hub genes. RESULTS: According to the RT-qPCR results, the expression of miR-302b-5p was pronouncedly decreased in 39 HCC tissue samples as compared to 39 non-cancerous liver tissue samples. The standard mean difference (SMD) values of all the samples used in the meta-analysis also indicated lower miR-302b-5p expression in the 558 HCC tissue samples than in the 286 non-cancerous liver tissue samples. ROC and sROC analyses showed that miR-302b-5p had good specificity and sensitivity for distinguishing HCC tissue from non-cancerous liver tissue. Bioinformatics analyses identified 227 putative genes, and these genes were evidently enriched in the processes of organelle fission, chromosome and chromatin binding and were centralized in a "lysosome" pathway. The PPI network indicated that DNA topoisomerase II alpha (TOP2 A) was the most prominent hub gene of miR-302b-5p in HCC. Interestingly, according to the TCGA and Genotype-Tissue Expression databases, the mRNA and protein expression of TOP2 A were both elevated in HCC tissue samples as compared to non-cancerous liver tissue samples, and the overall survival and disease-free survival revealed that a high level of TOP2 A might reflect poor HCC outcome. CONCLUSIONS: Our findings indicate that miR-302b-5p might suppress HCC progression, and TOP2 A might be a potential target of miR-302b-5p in HCC. However, in-depth in vivo and in vitro experiments are required to verify these findings and explore the mechanisms involved.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Fígado/metabolismo , MicroRNAs/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Simulação por Computador , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , MicroRNAs/genética
14.
Oncol Rep ; 41(6): 3244-3256, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942464

RESUMO

Nitidine chloride (NC), an inartificial bioactive alkaloid present in the root of Zanthoxylum nitidum (Roxb.) DC, is known for its versatile anti­inflammation and anticancer capabilities. The molecular mechanisms underlying its anticancer properties, however, remain obscure. The authors of the present study demonstrated the tumor suppressive effects of NC in a human liver cancer cell line using an MTT assay. The tumor suppressive capacity of NC was also analysed in a tumor xenograft nude mouse model. Changes in tumor cell gene expression profiles following NC treatment were detected by microarray; bioinformatics analysis demonstrated that differentially expressed genes were enriched in several cancer­associated pathways, including those initiated by transforming growth factor­ß and phosphatidylinositol 4,5­bisphosphate 3­kinase/RAC­α serine/threonine­protein kinase signaling. A Connectivity Map revealed that parthenolide, which has been identified previously as possessing anti­inflammatory and anticancer functions, was potentially extremely similar in molecular function to NC. By screening the data from The Cancer Genome Atlas project, eight genes that were upregulated in liver cancer and significantly suppressed by NC treatment were identified. Overexpression of these genes was closely associated with advanced tumor stage and poor differentiation status. This combination of upregulated genes enabled successful identification and prediction of prognosis for liver cancer. The findings of the present study suggest that NC could inhibit the growth of liver cancer cells through several potential molecular targets and signaling pathways.


Assuntos
Benzofenantridinas/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Proteínas de Neoplasias/genética , Animais , Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Análise em Microsséries , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Mol Med Rep ; 19(5): 4256-4270, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896874

RESUMO

Cinobufotalin is a chemical compound extracted from the skin of dried bufo toads that may have curative potential for certain malignancies through different mechanisms; however, these mechanisms remain unexplored in breast cancer. The aim of the present study was to investigate the antitumor mechanism of cinobufotalin in breast cancer by using microarray data and in silico analysis. The microarray data set GSE85871, in which cinobufotalin exerted influences on the MCF­7 breast cancer cells, was acquired from the Gene Expression Omnibus database, and the differentially expressed genes (DEGs) were analyzed. Subsequently, protein interaction analysis was conducted, which clarified the clinical significance of core genes, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used to analyze cinobufotalin­related pathways. The Connectivity Map (CMAP) database was used to select existing compounds that exhibited curative properties similar to those of cinobufotalin. A total of 1,237 DEGs were identified from breast cancer cells that were treated with cinobufotalin. Two core genes, SRC proto­oncogene non­receptor tyrosine kinase and cyclin­dependent kinase inhibitor 2A, were identified as serving a vital role in the onset and development of breast cancer, and their expression levels were markedly reduced following cinobufotalin treatment as detected by the microarray of GSE85871. It also was revealed that the 'neuroactive ligand­receptor interaction' and 'calcium signaling' pathways may be crucial for cinobufotalin to perform its functions in breast cancer. Conducting a matching search in CMAP, miconazole and cinobufotalin were indicated to possessed similar molecular mechanisms. In conclusion, cinobufotalin may serve as an effective compound for the treatment of a subtype of breast cancer that is triple positive for the presence of estrogen, progesterone and human epidermal growth factor receptor­2 receptors, and its mechanism may be related to different pathways. In addition, cinobufotalin is likely to exert its antitumor influences in a similar way as miconazole in MCF­7 cells.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Bufanolídeos/farmacologia , Perfilação da Expressão Gênica , Transdução de Sinais/efeitos dos fármacos , Transcriptoma , Neoplasias da Mama/patologia , Caspase 3/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Proteólise
16.
Oncol Rep ; 41(4): 2194-2208, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816530

RESUMO

MicroRNAs (miRNAs or miRs) contribute to the development of various malignant neoplasms, including glioblastoma multiforme (GBM). The present study aimed to explore the pathogenesis of GBM and to identify latent therapeutic agents for patients with GBM, based on an in silico analysis. Gene chips that provide miRNA expression profiling in GBM were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed miRNAs (DEMs) were also determined via the RobustRankAggreg algorithm. The target genes of DEMs were predicted and then intersected with GBM­associated genes that were collected from the Gene Expression Profiling Interactive Analysis. Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the overlapping genes were then performed. Simultaneously, a connectivity map (CMap) analysis was performed to screen for potential therapeutic agents for GBM. A total of 10 DEMs (hsa­miR­196a, hsa­miR­10b, hsa­miR­196b, hsa­miR­18b, hsa­miR­542­3p, hsa­miR­129­3p, hsa­miR­1224­5p, hsa­miR­876­3p and hsa­miR­770­5p) were obtained from three GEO gene chips (GSE25631, GSE42657 and GSE61710). Then, 1,720 target genes of the 10 miRNAs and 4,185 differently expressed genes in GBM were collected. By intersecting the aforementioned gene clusters, the present study identified 390 overlapping genes. GO and KEGG analyses of the 390 genes demonstrated that these genes were involved in certain cancer­associated biological functions and pathways. Eight genes [(GTPase NRas (NRAS), calcium/calmodulin­dependent protein kinase type II subunit Gamma (CAMK2G), platelet­derived growth factor receptor alpha (PDGFRA), calmodulin 3 (CALM3), cyclin­dependent kinase 6 (CDK6), calcium/calmodulin­dependent protein kinase type II subunit beta (CAMK2B), retinoblastoma­associated protein (RB1) and protein kinase C beta type (PRKCB)] that were centralized in the glioma pathway were selected for CMap analysis. Three chemicals (W­13, gefitinib and exemestane) were identified as putative therapeutic agents for GBM. In summary, the present study identified three miRNA­based chemicals for use as a therapy for GBM. However, more experimental data are needed to verify the therapeutic properties of these latent drugs in GBM.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Descoberta de Drogas/métodos , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , MicroRNAs/metabolismo , Androstadienos/química , Androstadienos/farmacologia , Androstadienos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Biologia Computacional , Gefitinibe/química , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular/métodos , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Transcriptoma/genética
17.
Onco Targets Ther ; 12: 953-958, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30774381

RESUMO

A combination of a Wilms' tumor (WT) and renal cell carcinoma (RCC) is an extremely rare pediatric renal neoplasm. Its prognosis and clinicopathological features remain unclarified. Herein, we describe a case of the coexistence of a WT and an RCC in a male child aged 5 years and 10 months. The child had symptoms of hematuria for more than 1 month. Although his irises were clear, medical imaging revealed a potential malignant tumor in the left kidney. The patient underwent resection of the left kidney. The pathological diagnosis was the coexistence of a WT and papillary RCC. Negative surgical margins were examined. One month following the resection, chemotherapy with vincristine plus dactinomycin (EE-4A regimen) was commenced. At the 69-month follow-up, there was no recurrence or metastasis. The coexistence of a WT and an RCC in the pediatric population is considered a rare pathological event. At present, there is no standard treatment for these renal neoplasms. In this study, the RCC treatment, which was the same as that applied in cases of WTs, was reasonable.

18.
Exp Mol Pathol ; 107: 141-157, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30768923

RESUMO

OBJECTIVE: To explore the clinical significance and potential molecular mechanism of endothelin receptor type B (EDNRB) in hepatocellular carcinoma (HCC). METHODS: Immunohistochemistry was used to detect EDNRB protein expression level in 67 HCC paraffin embedded tissues and adjacent tissues. Correlations between EDNRB expression level and clinicopathologic parameters were analyzed in our study. The expression level and clinical significance of EDNRB in HCC were also evaluated from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The cBioPortal for Cancer Genomics was employed to analyze the EDNRB related genes, and Gene Ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Protein-Protein Interaction (PPI) network were conducted for those EDNRB related genes. RESULTS: Lower expression level of EDNRB in HCC was verified by immunohistochemistry than adjacent tissues (P < 0.0001). The expression level of EDNRB in HCC tissues was lower than normal control liver tissues based on TCGA and GEO data (standard mean difference [SMD] = -1.48, 95% [confidence interval] CI: -1.63-(-1.33), Pheterogeneity = 0.116, I2 = 32.4%). Kaplan-Meier analysis showed that HCC patients with lower EDNRB expression were more prone to poor prognosis (P = .0041). The top terms of GO annotation in biological process, cellular component and molecular function were vasculature development, actin filament and transmembrane receptor protein kinase activity, respectively. The KEGG pathway enrichment analysis confirmed that EDNRB related genes mainly participated in Vascular smooth muscle contraction, cGMP-PKG signaling pathway and Focal adhesion pathways. The result of PPI network construction showed that KDR, VEGFC, FLT1, CDH5 and ADCY4 were possible to become the core genes of EDNRB related genes, which need further experiments to confirm. CONCLUSION: Our study provides novel findings and insights on the molecular pathogenesis of HCC from EDNRB view.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Receptor de Endotelina B/biossíntese , Adulto , Idoso , Carcinoma Hepatocelular/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor de Endotelina B/análise
19.
Aging (Albany NY) ; 11(2): 480-500, 2019 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-30661062

RESUMO

BACKGROUND: Papillary thyroid cancer (PTC) is the most common subtype of thyroid cancer, and inflammation relates significantly to its initiation and prognosis. Systematic exploration of the immunogenomic landscape therein to assist in PTC prognosis is therefore urgent. The Cancer Genome Atlas (TCGA) project provides a large number of genetic PTC samples that enable a comprehensive and reliable immunogenomic study. METHODS: We integrated the expression profiles of immune-related genes (IRGs) and progression-free intervals (PFIs) in survival in 493 PTC patients based on the TCGA dataset. Differentially-expressed and survival-associated IRGs in PTC patients were estimated a computational difference algorithm and COX regression analysis. The potential molecular mechanisms and properties of these PTC-specific IRGs were also explored with the help of computational biology. A new prognostic index based on immune-related genes was developed by using multivariable COX analysis. RESULTS: A total of 46 differentially expressed immune-related genes were significantly correlated with clinical outcome of PTC patients. Functional enrichment analysis revealed that these genes were actively involved in a cytokine-cytokine receptor interaction KEGG pathway. A prognostic signature based on RGs (AGTR1, CTGF, FAM3B, IL11, IL17C, PTH2R and SPAG11A) performed moderately in prognostic predictions and correlated with age, tumor stage, metastasis, number of lesions, and tumor burden. Intriguingly, the prognostic index based on IRGs reflected infiltration by several types of immune cells. CONCLUSIONS: Together, our results screened several IRGs of clinical significance, revealed drivers of the immune repertoire, and demonstrated the importance of a personalized, IRG-based immune signature in the recognition, surveillance, and prognosis of PTC.

20.
Pathol Res Pract ; 215(1): 177-194, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30473171

RESUMO

Liver cancer is one of the few tumors with a steadily increasing morbidity and mortality; hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. We combined the expression profiles of Chaperonin Containing T-complex 1 Subunit 3 (CCT3) in HCC tissues based on microarray and RNA-sequencing data. The CCT3 expression levels were extracted and examined based on 421 samples from The Cancer Genome Atlas (TCGA) (HCC, n = 371; non-HCC, n = 50) and 3851 samples from 31 microarray or RNA-sequencing datasets (HCC, n = 1975; non-tumor = 1876). We used a variety of meta-analytic methods, including SMD forest maps, sensitivity analysis, subgroup analysis and sROC curves, to confirm the final results. Meanwhile, database-derived immunohistochemistry data was used for validation. We also further explained the potential mechanism of CCT3 in HCC through signal pathway analyses and PPI network construction with the CCT3 co-expressed genes. The mRNA and protein expression of CCT3 in HCC tissues were higher than in non-HCC tissues. The expression of CCT3 differed between groups when grouped according to clinicopathological parameters, such as race, family history, and histological grade. The results of standardised mean difference (SMD) forest map and summary receiver operating characteristic (sROC) curve revealed that CCT3 was highly expressed in HCC tissues and had a high ability to distinguish between cancer tissues and non-cancer tissues. The main form of CCT3 gene alteration in HCC was mRNA up-regulation and amplification (23%), and the most common mutation type was missense. The mRNA expression of CCT3 in HCC was negatively correlated with DNA methylation. According to the Kyoto Encyclopedia of Genes and Genomes pathway analysis, CCT3 can influence HCC occurrence and development through cell cycle and DNA replication pathways. In summary, this study carries out the staging and prognostic analysis of HCC. It suggests that CCT3 might play an important part in the tumorigenesis and progression of HCC and may have a certain prognostic value in HCC. Moreover, CCT3 might represent a promising biomarker for HCC.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Transformação Celular Neoplásica/genética , Neoplasias Hepáticas/genética , Análise de Sequência de RNA , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/diagnóstico , Ciclo Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
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