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1.
Bioengineered ; 12(1): 1627-1641, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33949293

RESUMO

Hepatocellular carcinoma (HCC) is a leading cause of mortality in cancer patients, but the association between miR-125b-2-3p and the onset and prognosis of HCC has not been reported in previous studies; thus, the clinicopathological implications of miR-125b-2-3p in HCC require elaboration. To examine the expression of miR-125b-2-3p in HCC, both in-house RT-qPCR and public datasets were used to calculate the standard mean difference (SMD) and the summary receiver operating characteristic (sROC). MiR-125b-2-3p was markedly lower in HCC than in non-tumor tissue as assessed by the in-house RT-qPCR which was confirmed by the integrative analysis showing the SMD being -0.69 and the area under the curve (AUC) being 0.84 based on 1,233 cases of HCC and 630 cases of non-HCC controls. To gain a overview of the clinical value of miR-125b-2-3p in HCC, all possible datasets were integrated, and lower miR-125b-2-3p levels could lead to poorer differentiation and a more advanced clinical stage of HCC. The hazard ratio (HR) of miR-125b-2-3p was also calculated using a Cox proportional hazards model, and the miR-125b-2-3p level could act as an protective indication for the survival with the HR being 0.74 based on 586 cases of HCC. Furthermore, the effect of nitidine chloride (NC), a natural bioactive phytochemical alkaloid, on the regulation of miR-125b-2-3p and its potential targets was also investigated. The miR-125b-2-3p level was increased after NC treatment, while the expression of its potential target PRKCA was reduced. Above all, a low-expressed level of miR-125b-2-3p plays a tumor suppressive role in HCC.


Assuntos
Carcinoma Hepatocelular/genética , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , MicroRNAs/genética , Carcinoma Hepatocelular/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Masculino , MicroRNAs/metabolismo , Prognóstico , Curva ROC , Fatores de Risco
2.
PeerJ ; 8: e10458, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33354424

RESUMO

Background: Existing studies of PLK1 in cervical cancer had several flaws. The methods adopted by those studies of detecting PLK1 expression in cervical cancer were single and there lacks comprehensive evaluation of the clinico-pathological significance of PLK1 in cervical cancer. Methods: A total of 303 cervical tissue samples were collected for in-house tissue microarrays. Immunohistochemistry was performed for evaluating PLK1 expression between cervical cancer (including cervical squamous cell carcinoma (CESC) and cervical adenocarcinoma) and non-cancer samples. The Expression Atlas database was searched for querying PLK1 expression in different cervical cancer cell lines and different tissues in the context of pan-cancer. Standard mean difference (SMD) was calculated and the summarized receiver's operating characteristics (SROC) curves were plotted for integrated tissue microarrays, exterior high-throughput microarrays and RNA sequencing data as further verification. The effect of PLK1 expression on the overall survival, disease-free survival and event-free survival of cervical cancer patients was analyzed through Kaplan Meier survival curves for cervical cancer patients from RNA-seq and GSE44001 datasets. The gene mutation and alteration status of PLK1 in cervical cancer was inspected in COSMIC and cBioPortal databases. Functional enrichment analysis was performed for genes correlated with PLK1 from aggregated RNA-seq and microarrays. Results: A total of 963 cervical cancer samples and 178 non-cancer samples were collected from in-house tissue microarrays and exterior microarrays and RNA-seq datasets. The combined expression analysis supported overexpression of PLK1 in CESC, cervical adenocarcinoma and all types of cervical cancer (SMD = 1.59, 95%CI [0.56-2.63]; SMD = 2.99, 95%CI [0.75-5.24]; SMD = 1.57, 95% CI [0.85-2.29]) and the significant power of PLK1 expression in distinguishing CESC or all types of cervical cancer samples from non-cancer samples (AUC = 0.94, AUC = 0.92). Kaplan-Meier survival curves showed that the event-free survival rate of cervical cancer patients with higher expression of PLK1 was shorter than that of patients with lower PLK1 (HR = 2.020, P = 0.0197). Genetic alteration of PLK1 including missense mutation and mRNA low occurred in 6% of cervical cancer samples profiled in mRNA expression. Genes positively or negatively correlated with PLK1 were mainly assembled in pathways such as DNA replication, cell cycle, mismatch repair, Ras signaling pathway, melanoma, EGFR tyrosine kinase inhibitor resistance and homologous recombination (P < 0.05). Conclusions: Here, we provided sufficient evidence of PLK1 overexpression in cervical cancer. The overexpression of PLK1 in cervical cancer and the contributory effect of it on clinical progression indicated the hopeful prospect of PLK1 as a biomarker for cervical cancer.

3.
Cancer Med ; 9(21): 8004-8019, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32931665

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) remains one of the most common cancers worldwide and tends to be detected at an advanced stage. More effective biomarkers for HCC screening and prognosis assessment are needed and the mechanisms of HCC require further exploration. The role of MAOA in HCC has not been intensively investigated. METHODS: In-house tissue microarrays, genechips, and RNAsequencing datasets were integrated to explore the expression status and the clinical value of MAOA in HCC. Immunohistochemical staining was utilized to determine MAOA protein expression. Intersection genes of MAOA related co-expressed genes and differentially expressed genes were obtained to perform functional enrichment analyses. In vivo experiment was conducted to study the impact of traditional Chinese medicine nitidine chloride (NC) on MAOA in HCC. RESULTS: MAOA was downregulated and possessed an excellent discriminatory capability in HCC patients. Decreased MAOA correlated with poor prognosis in HCC patients. Downregulated MAOA protein was relevant to an advanced TNM stage in HCC patients. Co-expressed genes that positively related to MAOA were clustered in chemical carcinogenesis, where CYP2E1 was identified as the hub gene. In vivo experiment showed that nitidine chloride significantly upregulated MAOA in a nude mouse HCC model. CONCLUSIONS: A decreased MAOA level is not only correlated with aggressive behaviors in males but also serves as a promising biomarker for the diagnosis and prognosis of HCC patients. Moreover, MAOA may play a role in AFB1 toxic transformation through its synergistic action with co-expressed genes, especially CYP3A4. MAOA also serves as a potential therapy target of NC in HCC patients.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/enzimologia , Neoplasias Hepáticas/enzimologia , Monoaminoxidase/análise , Animais , Antineoplásicos Fitogênicos/farmacologia , Benzofenantridinas/farmacologia , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Bases de Dados Genéticas , Regulação para Baixo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos Nus , Monoaminoxidase/genética , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Valor Preditivo dos Testes , Mapas de Interação de Proteínas , RNA-Seq , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Pathol Res Pract ; 216(1): 152754, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31787478

RESUMO

Breast cancer (BC) is the most common cancer worldwide. However, the expression and potential mechanism of miR-375 in BC are still controversial. We first collected microRNA chips and microRNA sequencing data from multiple databases for analyzing the expression level of miR-375, and further exploring the target genes and underlying molecular mechanism in BC. miR-375 in BC was predominantly overexpressed compared with that in normal breast tissues (pooled standard mean difference [SMD] = 0.49; 95 % confidence interval [CI]: 0.24-0.73, p < 0.0001). Meanwhile, the overall pooled area under the curve (AUC) in the summary receiver operating characteristic (SROC) of miR-375 was 0.83 (95 % CI = 0.79-0.86) based on 2928 cases of BC patients and 816 cases of controls, while the diagnostic positive likelihood ratio (DLR) positive and the DLR negative value were 3.90 (95 % CI = 2.46-6.19) and 0.39 (95 % CI = 0.28-0.54), respectively. The hazard ratios (HRs) were 1.29 (95 % CI = 1.04-1.6, P = 0.02) and 1.23 (95 % CI = 0.89-1.7, P = 0.22) for the cohorts of METABRIC and The Cancer Genome Atlas (TCGA). In vitro study demonstrated that miR-375 inhibitor could suppress the cell growth and induce apoptosis of BC cells. A total of 107 overlapping genes from microarrays after miR-375 transfection, the TCGA RNA sequencing, the microarrays of Affymetrix platform, and online predicting software were selected as the prospective targets of miR-375 in BC. Based on Gene Ontology (GO) enrichment analysis, the potential targets of miR-375 were notable for their somatic stem cell division, plasma membrane, and proline-rich region binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway examination demonstrated that the targets were associated with the pathways of prion diseases, proteoglycans in cancer, and focal adhesion. Then, 107 targets of miR-375 in BC were used to construct a protein-protein interaction (PPI) network. Finally, EGFR, PRKCA, PPARA, ADIPOQ, and ITSN1 were found to be the hub genes of miR-375. These targets showed negative correlations with miR-375 level. The upregulated miR-375 might play an essential part in the tumorigenesis and progression of BC.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , Ativação Transcricional/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Simulação por Computador , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Mapas de Interação de Proteínas/genética , Curva ROC
6.
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.

7.
J Cancer ; 10(22): 5339-5354, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632479

RESUMO

Gastric cancer (GC) threatens human health worldwide and we performed this meta-analysis to evaluate the clinical value of Ki-67/MKI67 in patients with GC. The combined hazard ratio (HR), odds ratio (OR) and 95% confidence interval (95% CI) were calculated to assess the relationships of Ki-67/MKI67 expression with prognoses and clinicopathological characteristics. Genes co-expressed with MKI67 were collected for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein-protein interaction (PPI) network analyses. In total, 53 studies with 7078 patients were included in this study. The pooled HRs indicated that an elevated expression of Ki-67/MKI67 predicted an unfavorable overall survival (HR: 1.54, 95% CI: 1.33-1.78, P<0.0001) and disease-free survival (HR: 2.28, 95% CI: 1.43-3.64, P<0.0001) in GC patients. Additionally, in patients with advanced GC, a high Ki-67/MKI67 expression was also significantly connected with OS (HR: 1.37, 95% CI: 1.18-1.60, P<0.0001). The combined ORs showed that Ki-67/MKI67 expression was related to TNM stage (stage III/IV versus stage I/II: OR=1.93, 95% CI=1.34-2.78, P<0.0001), tumor differentiation (poor versus well/moderate: OR=1.94, 95% CI=1.32-2.85, P=0.001), lymph node metastasis (yes versus no: OR=1.67, 95% CI=1.23-2.25, P=0.001), distant metastasis (yes versus no: OR=1.67, 95% CI=1.24-2.26, P=0.001) and tumor invasion depth (T3/T4 versus Tis/T1/T2: OR=1.98, 95% CI=1.60-2.44, P<0.0001). The results of GO, KEGG pathway and PPI network analyses indicated that Ki-67/MKI67 may be involved in the development of GC via influencing P53 signaling pathway. Ki-67/MKI67 could be a potential indicator to predict the prognosis of patients with GC and identify high-risk cases. Detecting Ki-67/MKI67 expression in clinic may be helpful in optimizing individual treatment and further improving the survival expectancy of patients with GC.

8.
Cell Death Dis ; 10(9): 658, 2019 09 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.


Assuntos
Benzofenantridinas/farmacologia , Carcinoma Hepatocelular , Neoplasias Hepáticas Experimentais , RNA Circular , RNA Neoplásico , RNA-Seq , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/metabolismo , Camundongos , Camundongos Nus , RNA Circular/biossíntese , RNA Circular/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
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
10.
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
11.
Am J Transl Res ; 11(12): 7503-7522, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31934297

RESUMO

Nitidine chloride (NC) has reported tumor suppressive activities for various human cancers, including hepatocellular carcinoma (HCC). Nevertheless, the pharmacological mechanism of NC on HCC has not previously been elucidated. SMMC7721 HCC cell lines, before and after the treatment of NC, were injected into nude mice for a subcutaneous tumor xenograft model. MiRNA and mRNA sequencing were performed for both control and treated xenograft tissues to further analyze differential expressed miRNAs (DEmiRNAs) and mRNAs (DEmRNAs). The ten most significant DEmiRNAs were selected for prediction of transcription factors (TFs) and target genes. We constructed an interconnected network composed of TFs the ten most significant DEmiRNAs, the 100 most significant DEmRNAs, and selected target genes from online programs. Hub genes chosen from a protein-to-protein interaction network of hub genes were validated by correlation analysis, expression analysis, and Kaplan-Meier survival analysis. The five most up-regulated miRNAs (hsa-miR-628-5p, hsa-miR-767-5p, hsa-miR-767-3p, hsa-miR-1257, and hsa-miR-33b-3p) and the five most down-regulated miRNAs (hsa-miR-378d, hsa-miR-136-5p, hsa-miR-451a, hsa-miR-144-5p, and hsa-miR-378b) were singled out from the DEmiRNAs. Functional annotations indicated that potential target genes of the top five up-regulated miRNAs were mainly clustered in molecular processes concerning epithelial-to-mesenchymal transition. Hub genes, such as ITGA6 and ITGB4, were validated as up-regulated in HCC; both IFIT2 and IFIT3 were revealed by Kaplan-Meier survival curves as good prognostic factors for HCC. In summary, the regulating axes of NC-DEmiRNAs-DEmRNAs and TFs-DEmiRNAs-DEmRNAs in HCC that were discovered in this study may shed light on the possible molecular mechanism of NC in HCC.

12.
Cell Physiol Biochem ; 51(3): 1027-1040, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30476925

RESUMO

BACKGROUND/AIMS: The activating molecule in Beclin1-regulated autophagy (Ambra1) has been observed to be over-expressed in several cancers, but the clinical contribution of Ambra1 in breast cancer (BC) remains unknown. Hence, in this study, we conducted a comprehensive investigation into the expression, biological role, and underlying functional mechanism of Ambra1 in BC. METHODS: Microarray and RNA-seq datasets providing Ambra1 expression data were obtained from Gene Expression Omnibus (GEO), ArrayExpress, Oncomine, and The Cancer Genome Atlas (TCGA). Both standard mean deviation (SMD) and summary receiver operating characteristic methods were employed to assess Ambra1 expression in BC. We then silenced Ambra1 in MDA-MB-231 cells and performed in vitro experiments to explore the biological effects of Ambra1 on BC cells. Furthermore, differentially expressed genes (DEGs) after Ambra1 knock-down were profiled with a microarray and overlapped with the genes correlated with Ambra1 from Multi Experiment Matrix (MEM) and genes similar to Ambra1 from Gene Expression Profiling Interactive Analysis. These overlapping genes were collected for further bioinformatics analyses to investigate the underlying molecular mechanism of Ambra1 in BC. RESULTS: A total of 25 microarray and RNA-seq datasets involving 2460 breast cancer samples were included. The pooled results demonstrated that Ambra1 was markedly up-regulated in BC tissues (SMD=0.39, 95% CI=0.15-0.63; P=0.002), and the Ambra1 level was also significantly related to the progression of BC, especially metastasis status (P=0.004). In vitro experiments suggested that the proliferation of MDA-MB-231 cells transfected with Ambra1 short hairpin RNA (sh-RNA 2450) showed a decreasing trend at 48 h compared with the control (CK) group. However, apoptosis was similar in cells transfected with Ambra1 sh-RNAs and in the CK cells. Furthermore, we performed a microarray-based comparison of genes after Ambra1 knock-down. The 828 DEGs from microarray analysis were intersected with 4266 Ambra1 co-expressed genes from MEM. Eventually, the overlapped 183 genes were found to be enriched in several well-known cancer-related pathways, including the MAPK signaling pathway, chronic myeloid leukemia pathway, and VEGF signaling pathway. CONCLUSION: These results indicate that the level of Ambra1 up-regulation is clearly related to tumorigenesis and progression of BC, probably via influencing several vital pathways. However, this hypothesis needs to be validated with more in-depth experiments in the future.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Autofagia , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Perfilação da Expressão Gênica , Inativação Gênica , Humanos , Pessoa de Meia-Idade , Prognóstico
13.
Clin Drug Investig ; 38(10): 909-925, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30097905

RESUMO

BACKGROUND AND OBJECTIVES: Pharmacological control against ovarian serous cystadenocarcinoma has received increasing attention. The purpose of this study was to investigate multi-drug treatments as synergetic therapy for ovarian serous cystadenocarcinoma and to explore their mechanisms of action by the network pharmacology method. METHODS: Genes acting on ovarian serous cystadenocarcinoma were first collected from GEPIA and DisGeNET. Gene Ontology annotation, Kyoto Encyclopedia of Genes and Genomes pathway, Reactome pathway, and Disease Ontology analyses were then conducted. A connectivity map analysis was employed to identify compounds as treatment options for ovarian serous cystadenocarcinoma. Targets of these compounds were obtained from the Search Tool for Interacting Chemicals (STITCH). The intersections between the ovarian serous cystadenocarcinoma-related genes and the compound targets were identified. Finally, the Kyoto Encyclopedia of Genes and Genomes and Reactome pathways in which the overlapped genes participated were selected, and a correspondence compound-target pathway network was constructed. RESULTS: A total of 541 ovarian serous cystadenocarcinoma-related genes were identified. The functional enrichment and pathway analyses indicated that these genes were associated with critical tumor-related pathways. Based on the connectivity map analysis, five compounds (resveratrol, MG-132, puromycin, 15-delta prostaglandin J2, and valproic acid) were determined as treatment agents for ovarian serous cystadenocarcinoma. Next, 48 targets of the five compounds were collected. Following mapping of the 48 targets to the 541 ovarian serous cystadenocarcinoma-related genes, we identified six targets (PTGS1, FOS, HMOX1, CASP9, PPARG, and ABCB1) as therapeutic targets for ovarian serous cystadenocarcinoma by the five compounds. By analysis of the compound-target pathway network, we found the synergistic anti-ovarian serous cystadenocarcinoma potential and the underlying mechanisms of action of the five compounds. CONCLUSION: In summary, latent drugs against ovarian serous cystadenocarcinoma were acquired and their target actions and pathways were determined by the network pharmacology strategy, which provides a new prospect for medicamentous therapy for ovarian serous cystadenocarcinoma. However, further in-depth studies are indispensable to increase the validity of this study.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Cistadenocarcinoma Seroso/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Epitelial do Ovário/genética , Estudos de Coortes , Cistadenocarcinoma Seroso/genética , Sistemas de Liberação de Medicamentos/tendências , Feminino , Redes Reguladoras de Genes/genética , Humanos , Células MCF-7 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Resultado do Tratamento
14.
J Transl Med ; 16(1): 220, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30092792

RESUMO

BACKGROUND: Circular RNAs (circRNAs) have received increasing attention in human tumor research. However, there are still a large number of unknown circRNAs that need to be deciphered. The aim of this study is to unearth novel circRNAs as well as their action mechanisms in hepatocellular carcinoma (HCC). METHODS: A combinative strategy of big data mining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and computational biology was employed to dig HCC-related circRNAs and to explore their potential action mechanisms. A connectivity map (CMap) analysis was conducted to identify potential therapeutic agents for HCC. RESULTS: Six differently expressed circRNAs were obtained from three Gene Expression Omnibus microarray datasets (GSE78520, GSE94508 and GSE97332) using the RobustRankAggreg method. Following the RT-qPCR corroboration, three circRNAs (hsa_circRNA_102166, hsa_circRNA_100291 and hsa_circRNA_104515) were selected for further analysis. miRNA response elements of the three circRNAs were predicted. Five circRNA-miRNA interactions including two circRNAs (hsa_circRNA_104515 and hsa_circRNA_100291) and five miRNAs (hsa-miR-1303, hsa-miR-142-5p, hsa-miR-877-5p, hsa-miR-583 and hsa-miR-1276) were identified. Then, 1424 target genes of the above five miRNAs and 3278 differently expressed genes (DEGs) on HCC were collected. By intersecting the miRNA target genes and the DEGs, we acquired 172 overlapped genes. A protein-protein interaction network based on the 172 genes was established, with seven hubgenes (JUN, MYCN, AR, ESR1, FOXO1, IGF1 and CD34) determined from the network. The Gene Oncology, Kyoto Encyclopedia of Genes and Genomes and Reactome enrichment analyses revealed that the seven hubgenes were linked with some cancer-related biological functions and pathways. Additionally, three bioactive chemicals (decitabine, BW-B70C and gefitinib) based on the seven hubgenes were identified as therapeutic options for HCC by the CMap analysis. CONCLUSIONS: Our study provides a novel insight into the pathogenesis and therapy of HCC from the circRNA-miRNA-mRNA network view.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Redes Reguladoras de Genes , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , MicroRNAs/genética , RNA/genética , Algoritmos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sequência de Bases , Bases de Dados como Assunto , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , MicroRNAs/metabolismo , Anotação de Sequência Molecular , Mapas de Interação de Proteínas/genética , RNA/metabolismo , RNA Circular , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/genética
15.
Int J Oncol ; 53(5): 1897-1912, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30132517

RESUMO

The aim of the present study was to determine the role of topoisomerase 1 (TOP1) and topoisomerase 2A (TOP2A) in liver cancer (LC), and to investigate the inhibitory effect of nitidine chloride (NC) on these two topoisomerases. Immunohistochemistry (IHC) staining and microarray or RNA sequencing data mining showed markedly higher expression of TOP1 and TOP2A at the protein and mRNA levels in LC tissues compared with that in control non-tumor tissues. The prognostic values of TOP1 and TOP2A expression were also estimated based on data from The Cancer Genome Atlas. The elevated expression levels of TOP1 and TOP2A were closely associated with poorer overall survival and disease-free survival rates. When patients with LC were divided into high- and low-risk groups according to their prognostic index, TOP1 and TOP2A were highly expressed in the high-risk group. Bioinformatics analyses conducted on the co-expressed genes of TOP1 and TOP2A revealed that the topoisomerases were involved in several key cancer-related pathways, including the 'p53 pathway', 'pathway in cancer' and 'apoptosis signaling pathway'. Reverse transcription-quantitative polymerase chain reaction and IHC performed on triplicate tumor tissue samples from LC xenografts in control or NC-treated nude mice showed that NC treatment markedly reduced the protein and mRNA expression of TOP1 and TOP2A in LC tissues. Molecular docking studies further confirmed the direct binding of NC to TOP1 and TOP2A. In conclusion, the present findings indicate that TOP1 and TOP2A are oncogenes in LC and could serve as potential biomarkers for the prediction of the prognosis of patients with LC and for identification of high-risk cases, thereby optimizing individual treatment management. More importantly, the findings support TOP1 and TOP2A as potential drug targets of NC for the treatment of LC.


Assuntos
Benzofenantridinas/farmacologia , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo I/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Proteínas de Ligação a Poli-ADP-Ribose/genética , Animais , Biomarcadores Tumorais/genética , DNA Topoisomerases Tipo I/química , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/metabolismo , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular/métodos , Proteínas de Ligação a Poli-ADP-Ribose/química , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Cell Physiol Biochem ; 48(2): 540-555, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30021196

RESUMO

BACKGROUND/AIMS: Accumulated evidence indicates that lncRNA NEAT1 has important roles in various malignant tumors. In this study, we conducted a comprehensive analysis to explore the exact role of NEAT1 in hepatocellular carcinoma (HCC). METHODS: The effects of NEAT1 on cell proliferation, apoptosis, migration, and invasion were measured by in vitro experiments. The expression level and clinical value of NEAT1 in HCC was evaluated based on data from The Cancer Genome Atlas (TCGA), Oncomine, and in-house real-time quantitative (RT-qPCR). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) network analyses were conducted to investigate the potential molecular mechanisms of NEAT1. RESULTS: NEAT1 siRNA not only inhibited proliferation, migration, and invasion of HCC cells but also induced HCC cell apoptosis. A total of four records from TCGA, Oncomine, and RT-qPCR analysis were combined to assess the expression level of NEAT1 in HCC. The pooled standard mean deviation (SMD) indicated that NEAT1 was up-regulated in HCC (SMD = 0.54; 95% CI, 0.36-0.73; P < 0.0001). The area under the curve value of the summary receiver operating characteristic curve was 0.71. NEAT1 expression was also related to race (P = 0.025) and distant metastasis (P = 0.002). Additionally, the results of GO, KEGG pathway, and PPI network analyses suggest that NEAT1 may promote the progression of HCC by interacting with several tumor-related genes (SP1, MDM4, CREBBP, TRAF5, CASP8, TRAF1, KAT2A, and HIST4H4). CONCLUSIONS: NEAT1 contributes to the deterioration of HCC and provides a potential biomarker for the diagnosis and therapy of HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , RNA Longo não Codificante/metabolismo , Apoptose , Área Sob a Curva , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Proteínas de Ciclo Celular , Movimento Celular , Proliferação de Células , Mineração de Dados , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo
17.
Cell Physiol Biochem ; 48(3): 905-918, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30036873

RESUMO

BACKGROUND/AIMS: Long noncoding RNAs (lncRNAs) contribute to the development of multiple malignant tumors. Here, we focused on the biological function and underlying molecular mechanism of an lncRNA, nuclear-enriched abundant transcript 1 (NEAT1), in lung adenocarcinoma (LUAD). METHODS: In vitro experiments were conducted to determine the biological effects of NEAT1 in LUAD cells. A luciferase activity reporter assay was performed to corroborate the interaction between NEAT1 and miR-193a-3p. Data from Gene Expression Omnibus (GEO), Oncomine, The Cancer Genome Atlas (TCGA), and our in-house reverse transcription quantitative PCR (RT-qPCR) were combined to examine the expression of NEAT1 and miR-193a-3p in LUAD. To further explore the regulatory mechanism of NEAT1, we searched for putative target genes of miR-193a-3p from 12 online prediction databases and determined genes positively correlated with NEAT1 as candidate targets. Furthermore, we analyzed the expression of these selected genes using data from TCGA. RESULTS: In vitro experiments showed that knockdown of NEAT1 in LUAD cells markedly restrained cell proliferation, invasion, and migration and stimulated cell apoptosis. The dual-luciferase reporter assay demonstrated that miR-193a-3p directly targeted NEAT1 at its 3'-UTR. We then detected NEAT1 and miR-193a-3p in LUAD cells and normal lung epithelial cells and discovered high expression of NEAT1 and low expression of miR-193a-3p in LUAD cell lines. Simultaneously, the pooled results from the GEO, Oncomine, TCGA, and in-house RT-qPCR showed that the NEAT1 expression increased while the miR-193a-3p expression decreased in LUAD tissues versus normal lung tissues. Furthermore, the USF1 gene was not only upregulated in LUAD, but also positively correlated with NEAT1, suggesting that NEAT1 may function as a ceRNA to sponge miR-193a-3p and abrogate the inhibitory effect of miR-193a-3p on USF1. CONCLUSIONS: Our findings indicate that NEAT1 plays important roles in the occurrence and progression of LUAD. It may exert its role by acting as a ceRNA to regulate miR-193a-3p.


Assuntos
MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Regiões 3' não Traduzidas , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Apoptose , Área Sob a Curva , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Bases de Dados Factuais , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MicroRNAs/química , MicroRNAs/genética , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Curva ROC , Alinhamento de Sequência , Fatores Estimuladores Upstream/química , Fatores Estimuladores Upstream/genética , Fatores Estimuladores Upstream/metabolismo
18.
Int J Oncol ; 52(6): 1801-1814, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29620195

RESUMO

MicroRNAs (miRNAs or miRs) are highly conserved small noncoding RNA molecules involved in gene regulation. An increasing number of studies have demonstrated that miRNAs act as oncogenes or antioncogenes in various types of cancer, including breast cancer (BC). However, the exact role of miR­671­3p in BC has not yet been reported. In the present study, in vitro experiments were implemented to explore the effects of miR­671­3p on the proliferation and apoptosis of BC cells, and reverse transcription­quantitative polymerase chain reaction was conducted using in­house clinical BC samples to address the expression level and clinical value of miR­671­3p in BC. Simultaneously, miR­671­3p target genes were collected, and subsequent bioinformatics analyses were executed to probe the potential signaling pathway through which miR­671­3p influenced the occurrence and progression of BC. According to the results, the expression level of miR­671­3p was lower in BC tissues compared with that in adjacent non­tumorous tissues (P=0.048), and the area under the curve was 0.697 (95% confidence interval=0.538­0.856), with a sensitivity and specificity of 0.818 and 0.579, respectively. Forced miR­671­3p expression in the BC cell line MDA­MB­231 evidently arrested cell proliferation and induced cell apoptosis. Furthermore, in silico enrichment analyses suggested that miR­671­3p may be involved in the initiation and progression of BC through the targeting of genes associated with the Wnt signaling pathway. In conclusion, the present study findings suggested that miR­671­3p may function as a tumor suppressor in BC by influencing the Wnt signaling cascade, which provides a prospective molecular target for the therapy of BC.


Assuntos
Neoplasias da Mama/genética , Biologia Computacional/métodos , Regulação para Baixo , MicroRNAs/genética , Reação em Cadeia da Polimerase/métodos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas In Vitro , Estadiamento de Neoplasias , Estudos Prospectivos , Via de Sinalização Wnt
19.
Oncotarget ; 9(15): 12284-12303, 2018 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-29552310

RESUMO

In the present study, we conducted a comprehensive analysis on the clinical roles of p27 protein and p27 gene in digestive tract cancers (DTCs). First, we performed immunohistochemistry staining and found that p27 protein was down-regulated in DTCs. Then we collected 62 publications and calculated the combined hazard ratios (HRs), odds ratios (ORs) and 95% confidence intervals (95% CIs) to clarify the relationships of p27 protein expression with prognoses and clinicopathological parameters. The overall HRs indicated that the down-regulated p27 protein was an independent prognostic biomarker for overall survival (HR: 1.58, 95% CI: 1.38-1.81, P < 0.0001) but not for disease-free survival and cancer-specific survival. The combined ORs indicated that a low expression of p27 protein was positively related to lymph node metastasis (OR: 2.15, 95% CI: 1.57-2.96, P < 0.0001), distant metastasis (OR: 2.02, 95% CI: 1.12-3.63, P = 0.019) and pathology grading (OR: 2.14, 95% CI: 1.75-2.62, P < 0.0001). Additionally, 60 DTCs-related microarray and RNA-seq datasets were obtained to investigate the expression level and clinical value of p27 gene in DTCs patients. We found that the expression level of p27 gene in DTCs was similar to that in normal controls. And no significant associations of p27 gene expression with prognoses and clinicopathological factors were observed. In conclusion, according to our results, it was p27 protein, but not p27 gene, that can function as an effective biomarker to predict the clinical outcome in patients with DTCs. The down-regulation of p27 protein in DTCs may not result from the altered expression of p27 gene.

20.
Oncotarget ; 8(54): 92497-92521, 2017 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-29190933

RESUMO

Polo-like kinase 1 (PLK1) is a multi-functional protein and its aberrant expression is a driver of cancerous transformation and progression. To increase our understanding of the clinical value and potential molecular mechanism of PLK1 in gastric cancer (GC), we performed this comprehensive investigation. A total of 25 datasets and 12 publications were finally incorporated. Additional immunohistochemistry was conducted to validate the expression pattern of PLK1 in GC. The pooled standard mean deviation (SMD) indicated that PLK1 mRNA was up-regulated in GC (SMD=1.21, 95% CI: 0.65-1.77, P< 0.001). Similarly, the pooled odds ratio (OR) revealed that PLK1 protein was overexpressed in GC compared with normal gastric tissue (OR=12.12, 95% CI: 5.41-27.16, P<0.001). The area under the curve (AUC) of the summary receiver operating characteristic (SROC) curve was 0.86. Furthermore, our results demonstrated that GC patients with PLK1 overexpression were significantly associated with unfavorable overall survival (HR =1.54, 95% CI: 1.30-1.83, P<0.001), lymph node metastasis (OR = 1.78, 95% CI: 1.13-2.80, P=0.013) and advanced TNM stage (OR=1.48, 95% CI: 1.02-2.15, P=0.038). Altogether, 100 similar genes were identified by Gene Expression Profiling Interactive Analysis (GEPIA) and further with gene-set enrichment analysis. These genes were related to gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways relevant to the cell cycle. Gene set enrichment analysis (GSEA) indicated that PLK1 is associated with various cancer-related pathways. Collectively, this study suggests that PLK1 overexpression could play vital roles in the carcinogenesis and deterioration of GC via regulating tumor-related pathways.

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