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1.
Artigo em Inglês | MEDLINE | ID: mdl-34619053

RESUMO

Background: To date, the clinical management of advanced hepatocellular carcinoma (HCC) patients remains tough and the mechanisms of E2F transcription factor 1 (E2F1) underlying HCC are obscure. Materials and Methods: Our study integrated datasets mined from several public databases to comprehensively understand the deregulated expression status of E2F1. Tissue microarrays and immunohistochemistry staining was used to validate E2F1 expression level. The prognostic value of E2F1 was assessed. In-depth subgroup analyses were implemented to compare the differentially expressed levels of E2F1 in HCC patients with various tumor stages. Functional enrichments were used to address the predominant targets of E2F1 and shedding light on their potential roles in HCC. Results: We confirmed the elevated expression of E2F1 in HCC. Subgroup analyses indicated that elevated E2F1 level was independent of various stages in HCC. E2F1 possessed moderate discriminatory capability in differentiating HCC patients from non-HCC controls. Elevated E2F1 correlated with Asian race, tumor classification, neoplasm histologic grade, eastern cancer oncology group, and plasma AFP levels. Furthermore, high E2F1 correlated with poor survival condition and pooled HR signified E2F1 as a risk factor for HCC. Enrichment analysis of differentially expressed genes, coexpressed genes, and putative targets of E2F1 emphasized the importance of cell cycle pathway, where CCNE1 and CCNA2 served as hub genes. Conclusions: We confirmed the upregulation of E2F1 and explored the prognostic value of E2F1 in HCC patients. Two putative targeted genes (CCNE1 and CCNA2) of E2F1 were identified for their potential roles in regulating cell cycle and promote antiapoptotic activity in HCC patients.

2.
BMC Cancer ; 21(1): 996, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488675

RESUMO

BACKGROUND: Esophageal cancer is a common malignant tumor and its 5-year survival rate is much lower than 30% due to its invasiveness and pronounced metastasis ability, as well as the difficulty in early diagnosis. This study aimed to elucidate the molecular mechanism of ubiquitin conjugating enzyme E2 C (UBE2C) in esophageal squamous cell carcinoma (ESCC). METHODS: In this study, we conducted a comprehensive evaluation of the UBE2C expression in ESCC by collecting the protein and mRNA expression data (including in-house RNA-seq, in-hosue immunohistochemistry, TCGA-GTEx RNA-seq and tissue microarray) to calculate a combined standardized mean difference (SMD) and summary receiver operating characteristic curve (sROC). Kaplan-Meier (K-M) method was used for survival analysis. We also explored the mechanism of UBE2C in ESCC by combing the differentially expressed genes (DEGs) of ESCC, related-genes of UBE2C in ESCC and the putative miRNAs and lncRNAs which may regulate UBE2C. RESULTS: UBE2C protein and mRNA were highly expressed in ESCC tissues (including 772 ESCC tissue samples and 1837 non-cancerous tissue control samples). The pooled SMD of UBE2C expression values was 1.98 (95% CI: 1.51-2.45, p < 0.001), and the the area under the curve (AUC) of the sROC was 0.93 (95% CI: 0.90-0.95). The results of survival analysis suggested that UBE2C is likely to play different roles in different stages of the ESCC. Pathway anaylsis showed that UBE2C mainly influenced the biological function of esophageal cancer by synergistic effects with CDK1, PTTG1 and SKP2. We also constructed a potential UBE2C-related ceRNA network for ESCC (HCP5/has-miR-139-5p/UBE2C). CONCLUSION: UBE2C mRNA and protein level were highly expressed in ESCC and UBE2C was likely to play different roles in different stages of the ESCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , RNA-Seq/métodos , Enzimas de Conjugação de Ubiquitina/metabolismo , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Biologia Computacional , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Prognóstico , RNA Longo não Codificante/genética , Taxa de Sobrevida , Enzimas de Conjugação de Ubiquitina/genética
3.
Bioengineered ; 12(1): 4054-4069, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34369278

RESUMO

During the pandemic of the coronavirus disease 2019, there exist quite a few studies on angiotensin-converting enzyme 2 (ACE2) and SARS-CoV-2 infection, while little is known about ACE2 in hepatocellular carcinoma (HCC). The detailed mechanism among ACE2 and HCC still remains unclear, which needs to be further investigated. In the current study with a total of 6,926 samples, ACE2 expression was downregulated in HCC compared with non-HCC samples (standardized mean difference = -0.41). With the area under the curve of summary receiver operating characteristic = 0.82, ACE2 expression showed a better ability to differentiate HCC from non-HCC. The mRNA expression of ACE2 was related to the age, alpha-fetoprotein levels and cirrhosis of HCC patients, and it was identified as a protected factor for HCC patients via Kaplan-Meier survival, Cox regression analyses. The potential molecular mechanism of ACE2 may be relevant to catabolic and cell division. In all, decreasing ACE2 expression can be seen in HCC, and its protective role for HCC patients and underlying mechanisms were explored in the study.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , Carcinoma Hepatocelular/genética , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Proteínas de Neoplasias/genética , Receptores Virais/genética , alfa-Fetoproteínas/genética , Fatores Etários , Idoso , Enzima de Conversão de Angiotensina 2/metabolismo , Área Sob a Curva , COVID-19/virologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/mortalidade , Cirrose Hepática/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/classificação , Proteínas de Neoplasias/metabolismo , Fatores de Proteção , Mapeamento de Interação de Proteínas , Curva ROC , Receptores Virais/metabolismo , SARS-CoV-2/patogenicidade , Análise de Sobrevida , alfa-Fetoproteínas/metabolismo
4.
Bioengineered ; 12(1): 4289-4303, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34304715

RESUMO

Hepatoblastoma is a kind of extreme malignancy frequently diagnosed in children. Although surgical resection is considered as the first-line treatment for hepatoblastoma, a relatively large population of patients have lost the preferred opportunity for surgery. Administration of locoregional ablation enables local tumor control but with the deficiency of insufficient ablation, residual tumor, and rapid progression. In this study, we integrated 219 hepatoblastoma and 121 non-cancer liver tissues to evaluate the expression of NR2F6, from which a higher NR2F6 level was found in hepatoblastoma compared with non-cancer livers with a standard mean difference (SMD) of 1.04 (95% CI: 0.79, 1.29). The overexpression of NR2F6 also appeared to be an efficient indicator in distinguishing hepatoblastoma tissues from non-cancer liver tissues from the indication of a summarized AUC of 0.90, with a pooled sensitivity of 0.76 and a pooled specificity of 0.89. Interestingly, nude mouse xenografts provided direct evidence that overexpressed NR2F6 was also detected in residual tumor compared to untreated hepatoblastoma. Chromatin immunoprecipitation-binding data in HepG2 cells and transcriptome analysis of HepG2 xenografts were combined to identify target genes regulated by NR2F6. We finally selected 150 novel target genes of NR2F6 in residual tumor of incomplete ablation, and these genes appeared to be associated with the biological regulation of lipid metabolism-related pathway. Accordingly, targeting NR2F6 holds a therapeutic promise in treating residual recurrent hepatoblastoma after incomplete ablation.

5.
Med Sci Monit ; 27: e928800, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33622998

RESUMO

BACKGROUND Hepatocellular carcinoma (HCC) causes a heavy disease burden worldwide. Cell division cycle 45 (Cdc45) and its encoding gene (CDC45) have been studied for a long time, but their expression patterns and roles in liver carcinogenesis and advanced HCC deterioration are still incompletely understood. This study integrated tissue microarray and bioinformatics analyses to explore the expression and clinical value of CDC45 and Cdc45 in HCC. MATERIAL AND METHODS In HCC, the expression and relationships with clinic-pathological parameters of CDC45 and Cdc45 were investigated by integrating the RNA-sequencing data, downloaded from The Cancer Genome Atlas and Oncomine databases, and tissue microarray with immunohistochemistry staining. Co-expressed genes and genetic alterations of CDC45 separately obtained from Oncomine and cBioPortal databases were identified to shed light on the potential mechanisms of CDC45 in HCC. RESULTS CDC45 and Cdc45 were both overexpressed in HCC tissues, and the CDC45 level progressively increased from stage I to III. The survival outcomes of the group with high CDC45 expression were significantly worse compared with the group with low expression. Amplification and deep deletion were 2 major significant alteration types in HCC patients, and the outcomes were worse in patients with altered versus unaltered CDC45. NUDT1, E2F1, CCNE2, MCM5, and CENPM were identified as the most significantly co-expressed genes. CONCLUSIONS CDC45 and Cdc45 were both upregulated in HCC, and increased expression levels and genetic alternations of CDC45 were correlated with worse prognosis in HCC patients. CDC45 may promote HCC by co-expressing with NUDT1, E2F1, CCNE2, MCM5, and CENPM.


Assuntos
Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular/genética , Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular/metabolismo , Biologia Computacional/métodos , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Prognóstico , Análise de Sequência de RNA , Transcriptoma
6.
Technol Cancer Res Treat ; 19: 1533033820979670, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33327879

RESUMO

Existing reports have demonstrated that miR-199a-3p plays a role as a tumor suppressor in a variety of human cancers. This study aims to further validate the expression of miR-199a-3p in HCC and to explore its underlying mechanisms by using multiple data sets. Chip data or sequencing data and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were integrated to assess the expression of miR-199a-3p in HCC. The potential targets and transcription factor regulatory network of miR-199a-3p in HCC were determined and possible biological mechanism of miR-199a-3p was analyzed with bioinformatics methods. In the results, miR-199a-3p expression was significantly lower in HCC tissues compared to normal tissues according to chip data or sequencing data and qRT-PCR. Moreover, 455 targets of miR-199a-3p were confirmed, and these genes were involved in the PI3K-Akt signaling pathway, pathways in cancer, and focal adhesions. LAMA4 was considered a key target of miR-199a-3p. In CMTCN, 11 co-regulatory pairs, 3 TF-FFLs, and 2 composite-FFLs were constructed. In conclusion, miR-199a-3p was down regulated in HCC and LAMA4 may be a potential target of miR-199a-3p in HCC.

7.
Med Sci Monit ; 26: e926273, 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33104528

RESUMO

BACKGROUND Bladder carcinoma (BLCA) is a leading cause of cancer-related deaths worldwide. The aim of this work was to develop an accurate stratification in predicting the prognosis and directing the treatment of BLCA patients based on small nucleolar RNAs (snoRNAs). MATERIAL AND METHODS Expression profiles of snoRNAs were downloaded from the SNORic database. The expression profiles and clinical outcomes of BLCA patients were analyzed. Survival-associated snoRNAs were identified and used to develop a novel risk score classifier. Genes in the whole genome that were significantly correlated with the included prognostic snoRNAs were used for functional enrichment analysis. RESULTS The results showed that age, American Joint Committee on Cancer (AJCC) stage, and tumor status were significantly correlated with overall survival (OS) of BLCA patients. We selected 12 survival-associated snoRNAs to build a prognostic signature. Patients were separated into high- and low-risk groups based on the median value of the risk score. Patients in the high-risk group and low-risk group have distinct clinical outcomes. The AJCC TNM stage showed moderate utility as a prognostic indicator for clinical outcome prediction. Then, clinical parameters and risk scores were entered in multivariate Cox analysis. Notably, the prognostic signature remained an independent significant prognostic risk factor. The pathway analysis suggested that these genes were enriched in several types of cancer and "Focal adhesion" pathways. CONCLUSIONS The prognostic signature defined by expression profiles of 12 survival-associated snoRNAs appears to be an excellent predictor of the clinical outcome of BLCA patients.


Assuntos
Carcinoma/diagnóstico , RNA Nucleolar Pequeno/metabolismo , Neoplasias da Bexiga Urinária/diagnóstico , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma/epidemiologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/epidemiologia
8.
Comput Biol Chem ; 89: 107383, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33032037

RESUMO

RUNX family transcription factor 2 (RUNX2) overexpression has been found in various human malignancies. However, the expression levels of RUNX2 mRNA and protein in lung adenocarcinoma (LUAD) were not investigated. This study aims to thoroughly analysis the expression level and potential mechanisms of RUNX2 mRNA in LUAD. We applied in-house immunohistochemistry, high-throughput RNA-sequencing, and gene microarrays to comprehensively investigate the expression level of RUNX2 in LUAD. A pool standard mean difference (SMD) and summary receiver operating characteristic curves (SROC) were calculated to assess the integrated expression value of RUNX2 in LUAD. The hazard ratios (HRs) were integrated to evaluate the overall prognostic effect of RUNX2 on the LUAD patients. The differentially expressed genes (DEGs) of LUAD, the potential target genes of RUNX2, and its co-expressed genes were overlapped to obtain a set of specific genes for GO and KEGG enrichment analyses. RUNX2 overexpression in LUAD was validated using a large number of cases (2 418 LUAD and 1 574 non-tumor lung samples). The pooled SMD was 0.85 (95 % CI: 0.64-1.05) and the area under the curve (AUC) of the SROC was 0.86 (95 %CI: 0.83-0.89). The integrated HR was 1.20 [1.04-1.38], indicating that increased expression of RUNX2 was an independent risk factor for the poor survival of the LUAD patients. RUNX2 and its transcriptionally regulates potential target genes may promote cell proliferation and drug resistance of LUAD by modulating the cell cycle and MAPK signaling pathways. RUNX2 can provide new research directions for targeted drug therapy and drug resistance for LUAD treatment.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias Pulmonares/metabolismo , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/patologia , Proliferação de Células/fisiologia , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Imuno-Histoquímica , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases/fisiologia , Prognóstico , RNA Mensageiro/análise , Transcrição Genética/fisiologia , Regulação para Cima
9.
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.

10.
Int J Oncol ; 57(1): 122-138, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32319600

RESUMO

SAC3 domain containing 1 (SAC3D1) has been reported to be involved in numerous types of cancer. However, the role of SAC3D1 in GC has not yet been elucidated. In the present study, the mRNA expression level of SAC3D1 between GC and normal tissues were assessed with a continuous variable meta­analysis based on multiple datasets from public databases. The protein expression level of SAC3D1 in GC and normal tissues was assessed by an in­house immunohistochemistry (IHC). The association between SAC3D1 expression and some clinical parameters was assessed based on the TCGA and IHC data. Survival analysis was performed to assess the association between SAC3D1 expression and the survival of GC patients. The co­expressed genes of SAC3D1 were determined by integrating three online tools, and the enrichment analyses were performed to determine SAC3D1­related pathways and hub co­expressed genes. SAC3D1 was significantly upregulated in GC tumor tissues in comparison to normal tissues with the SMD being 0.45 (0.12, 0.79). The IHC results also indicated that SAC3D1 protein expression in GC tissues was markedly higher than in normal tissues. The SMD following the addition of the IHC data was 0.59 (0.11, 1.07). The protein levels of SAC3D1 were positively associated with the histological grade, T stage and N stage of GC (P<0.001). The TCGA data also revealed that the SAC3D1 mRNA level was significantly associated with the N stage (P<0.001). Moreover, prognosis analysis indicated that SAC3D1 was closely associated with the prognosis of patients with GC. Moreover, 410 co­expressed genes of SAC3D1 were determined, and these genes were mainly enriched in the cell cycle. In total, 4 genes (CDK1, CCNB1, CCNB2 and CDC20) were considered key co­expressed genes. On the whole, these findings demonstrate that SAC3D1 is highly expressed in GC and may be associated with the progression of GC.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas Repressoras/metabolismo , Neoplasias Gástricas/diagnóstico , Estômago/patologia , Biomarcadores Tumorais/análise , Biologia Computacional , Conjuntos de Dados como Assunto , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , RNA-Seq , Proteínas Repressoras/análise , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Regulação para Cima
11.
PeerJ ; 8: e8409, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32095323

RESUMO

Background: Hepatocellular carcinoma (HCC) is the second-highest cause of malignancy-related death worldwide, and many physiological and pathological processes, including cancer, are regulated by microRNAs (miRNAs). miR-193a-3p is an anti-oncogene that plays an important part in health and disease biology by interacting with specific targets and signals. Methods: In vitro assays were performed to explore the influences of miR-193a-3p on the propagation and apoptosis of HCC cells. The sequencing data for HCC were obtained from The Cancer Genome Atlas (TCGA), and the expression levels of miR-193a-3p in HCC and non-HCC tissues were calculated. The differential expression of miR-193a-3p in HCC was presented as standardized mean difference (SMD) with 95% confidence intervals (CIs) in Stata SE. The impact of miR-193a-3p on the prognoses of HCC patients was determined by survival analysis. The potential targets of miR-193a-3p were then predicted using miRWalk 2.0 and subjected to enrichment analyses, including Gene Ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Protein-Protein Interaction (PPI) network analysis. The interaction between miR-193a-3p and one predicted target, Cyclin D1 (CCND1), was verified by dual luciferase reporter assays and Pearson correlation analysis. Results: MiR-193a-3p inhibited the propagation and facilitated the apoptosis of HCC cells in vitro. The pooled SMD indicated that miR-193a-3p had a low level of expression in HCC (SMD: -0.88, 95% CI [-2.36 -0.59]). Also, HCC patients with a higher level of miR-193a-3p expression tended to have a favorable overall survival (OS: HR = 0.7, 95% CI [0.43-1.13], P = 0.14). For the KEGG pathway analysis, the most related pathway was "proteoglycans in cancer", while the most enriched GO term was "protein binding". The dual luciferase reporter assays demonstrated the direct interaction between miR-193a-3p and CCND1, and the Pearson correlation analysis suggested that miR-193a-3p was negatively correlated with CCND1 in HCC tissues (R =  - 0.154, P = 0.002). Conclusion: miR-193a-3p could suppress proliferation and promote apoptosis by targeting CCND1 in HCC cells. Further, miR-193a-3p can be used as a promising biomarker for the diagnosis and treatment of HCC in the future.

12.
J Cancer ; 11(6): 1542-1554, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32047561

RESUMO

Alternative splicing (AS) is a major mechanism that greatly enhanced the diversity of proteome. Mounting evidence demonstrated that aberration of AS are important steps for the initiation and progression of human cancers. Here, we comprehensively investigated the association between whole landscape of AS profiles and the survival outcome of renal cell carcinoma (RCC) patients using RNA-seq data from TCGA SpliceSeq. Because of the limited number size of deaths in kidney chromophobe renal cell carcinoma (KICH) and papillary renal cell carcinoma (KIRP) TCGA cohorts, we only conducted survival analysis in kidney clear renal cell carcinoma (KIRC). We further constructed prognostic index (PI) based on prognosis-related AS events and built correlation network for splicing factors and prognosis-related AS events. According to the results, a total of 5351 AS events in 3522 genes were significantly correlated with the overall survival (OS) of kidney clear cell renal cell carcinoma (KIRC) patients. Seven of the PI models exhibited preferable prognosis-predicting capacity for KIRC with PI-ALL reaching the highest area under curve value of 0.875. The splicing regulatory network between splicing factors and prognosis-related AS events depicted a tangled web of relationships between them. One of the splicing factors: KHDRBS3 was validated by immunohistochemistry to be down-regulated in KIRC tissues. In conclusion, the powerful efficiency of risk stratification of PI models indicated the potential of AS signature as promising prognostic markers for KIRC and the splicing regulation network provided possible genetic mechanism of KIRC.

13.
BMC Med Genomics ; 13(1): 3, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906958

RESUMO

BACKGROUND: MiR-182-5p, a cancer-related microRNA (miRNA), modulates tumorigenesis and patient outcomes in various human malignances. This study interroted the clinicopathological significance and molecular mechanisms of miR-182-5p in non-small cell lung cancer (NSCLC). METHODS: The clinical significance of miR-182-5p in NSCLC subtypes was determined based on an analysis of 124 samples (lung adenocarcinomas [LUADs], n = 101; lung squamous cell carcinomas [LUSCs], n = 23) obtained from NSCLC patients and paired noncancer tissues and an analysis of data obtained from public miRNA-seq database, miRNA-chip database, and the scientific literature. The NSCLC samples (n = 124) were analyzed using the real-time quantitative polymerase chain reaction (RT-qPCR). Potential targets of miR-182-5p were identified using lists generated by miRWalk v.2.0, a comprehensive atlas of predicted and validated targets of miRNA-target interactions. Molecular events of miR-182-5p in NSCLC were unveiled based on a functional analysis of candidate targets. The association of miR-182-5p with one of the candidate target genes, homeobox A9 (HOXA9), was validated using in-house RT-qPCR and dual-luciferase reporter assays. RESULTS: The results of the in-house RT-qPCR assays analysis of data obtained from public miRNA-seq databases, miRNA-chip databases, and the scientific literature all supported upregulation of the expression level of miR-182-5p level in NSCLC. Moreover, the in-house RT-qPCR data supported the influence of upregulated miR-182-5p on malignant progression of NSCLC. In total, 774 prospective targets of miR-182-5p were identified. These targets were mainly clustered in pathways associated with biological processes, such as axonogenesis, axonal development, and Ras protein signal transduction, as well as pathways involved in axonal guidance, melanogenesis, and longevity regulation, in multiple species. Correlation analysis of the in-house RT-qPCR data and dual-luciferase reporter assays confirmed that HOXA9 was a direct target of miR-182-5p in NSCLC. CONCLUSIONS: The miR-182-5p expression level was upregulated in NSCLC tissues. MiR-182-5p may exert oncogenic influence on NSCLC through regulating target genes such as HOXA9.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Proteínas de Homeodomínio , Neoplasias Pulmonares , MicroRNAs , Proteínas de Neoplasias , RNA Neoplásico , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Simulação por Computador , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , RNA-Seq , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
14.
Eur Radiol ; 30(1): 547-557, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31396730

RESUMO

OBJECTIVES: To determine the integrative value of contrast-enhanced computed tomography (CECT), transcriptomics data and clinicopathological data for predicting the survival of bladder urothelial carcinoma (BLCA) patients. METHODS: RNA sequencing data, radiomics features and clinical parameters of 62 BLCA patients were included in the study. Then, prognostic signatures based on radiomics features and gene expression profile were constructed by using least absolute shrinkage and selection operator (LASSO) Cox analysis. A multi-omics nomogram was developed by integrating radiomics, transcriptomics and clinicopathological data. More importantly, radiomics risk score-related genes were identified via weighted correlation network analysis and submitted to functional enrichment analysis. RESULTS: The radiomics and transcriptomics signatures significantly stratified BLCA patients into high- and low-risk groups in terms of the progression-free interval (PFI). The two risk models remained independent prognostic factors in multivariate analyses after adjusting for clinical parameters. A nomogram was developed and showed an excellent predictive ability for the PFI in BLCA patients. Functional enrichment analysis suggested that the radiomics signature we developed could reflect the angiogenesis status of BLCA patients. CONCLUSIONS: The integrative nomogram incorporated CECT radiomics, transcriptomics and clinical features improved the PFI prediction in BLCA patients and is a feasible and practical reference for oncological precision medicine. KEY POINTS: • Our radiomics and transcriptomics models are proved robust for survival prediction in bladder urothelial carcinoma patients. • A multi-omics nomogram model which integrates radiomics, transcriptomics and clinical features for prediction of progression-free interval in bladder urothelial carcinoma is established. • Molecular functional enrichment analysis is used to reveal the potential molecular function of radiomics signature.


Assuntos
Nomogramas , Tomografia Computadorizada por Raios X/métodos , Transcriptoma/genética , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/genética , Adulto , Meios de Contraste , Feminino , Humanos , Masculino , Prognóstico , Intensificação de Imagem Radiográfica/métodos , Fatores de Risco , Análise de Sobrevida , Bexiga Urinária/diagnóstico por imagem , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/patologia
15.
IET Syst Biol ; 14(6): 314-322, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33399095

RESUMO

Basing on alternative splicing events (ASEs) databases, the authors herein aim to explore potential prognostic biomarkers for cervical squamous cell carcinoma (CESC). mRNA expression profiles and relevant clinical data of 223 patients with CESC were obtained from The Cancer Genome Atlas (TCGA). Correlated genes, ASEs and percent-splice-in (PSI) were downloaded from SpliceSeq, respectively. The PSI values of survival-associated alternative splicing events (SASEs) were used to construct the basis of a prognostic index (PI). A protein-protein interaction (PPI) network of genes related to SASEs was generated by STRING and analysed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Consequently, 41,776 ASEs were discovered in 19,724 genes, 2596 of which linked with 3669 SASEs. The PPI network of SASEs related genes revealed that TP53 and UBA52 were core genes. The low-risk group had a longer survival period than high-risk counterparts, both groups being defined according to PI constructed upon the top 20 splicing events or PI on the overall splicing events. The AUC value of ROC reached up to 0.88, demonstrating the prognostic potential of PI in CESC. These findings suggested that ASEs involve in the pathogenesis of CESC and may serve as promising prognostic biomarkers for this female malignancy.


Assuntos
Processamento Alternativo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/genética , Biomarcadores Tumorais/genética , Feminino , Redes Reguladoras de Genes , Humanos , Prognóstico
16.
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.

17.
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.

18.
Am J Transl Res ; 11(8): 4835-4850, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31497203

RESUMO

PURPOSE: Lung adenocarcinoma (LUAD) of non-small cell lung cancer (NSCLC) is a highly prevalent cancer with high mortality. The gene basigin (BSG) is strongly expressed in certain tumors. This study investigated the expression level of BSG in LUAD and its role in the poor prognosis of LUAD. METHODS: The mRNA expression of BSG in LUAD was from GEO, Oncomine and TCGA database. Prognostic data were provided by SurvExpress. The expression of BSG protein was detected by immunohistochemistry (IHC). Cell function experiments of viability, proliferation and apoptosis assays were performed in A549. Clustering analysis of BSG co-expressed genes was generated by Gene Ontology (GO) Enrichment, KEGG pathway and protein-protein interaction (PPI) network. RESULTS: BSG mRNA level was significantly over-expressed in LUAD (pooled SMD = 0.564, 0.448-0.681, P<0.001). The analysis in SurvExpress revealed that high expression of BSG indicated significantly poor prognosis (pooled HR = 1.20, 1.10-1.30, P<0.0001). IHC assay also showed that BSG protein expression was significantly up-regulated in LUAD (P<0.001), and positive BSG expression was notably associated with higher pathology grade (P = 0.041) and lymphatic metastasis (P = 0.014). Moreover, BSG can enhance the viability and proliferation ability (both P<0.001) and weaken cell apoptosis (P<0.001) in A549. The most enriched GO terms in the co-expressed genes of BSG were translation related enrichment. The KEGG pathway showed that these genes were markedly involved in Ribosome pathways. CONCLUSION: Up-regulated BSG in LUAD is related to advanced progression and poor prognosis by influencing cell viability, proliferation and apoptosis. BSG could be a potential biomarker for the targeted therapy of LUAD.

19.
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
20.
J Transl Med ; 17(1): 283, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31443718

RESUMO

BACKGROUND: Surgery, adjuvant chemotherapy, and radiotherapy are the primary treatment options for soft tissue sarcomas (STSs). However, identifying ways to improve the prognosis of patients with STS remains a considerable challenge. Evidence shows that the dysregulation of alternative splicing (AS) events is involved in tumor pathogenesis and progression. The present study objective was to identify survival-associated AS events that could serve as prognostic biomarkers and potentially serve as tumor-selective STS drug targets. METHODS: STS-specific 'percent spliced in' (PSI) values for splicing events in 206 STS samples were downloaded from The Cancer Genome Atlas SpliceSeq® database. Prognostic analyses were performed on seven types of AS events to determine their prognostic value in STS patients, for which prediction models were constructed with the risk score formula [Formula: see text]. Prediction models were also constructed to determine the prognostic value of AS events, and Spearman's rank correlation coefficients were calculated to determine the degree of correlation between splicing factor expression and the PSI values. RESULTS: A total 10,439 events were found to significantly correlate with patient survival rates. The area under the time-dependent receiver operating characteristic curve for the prognostic predictor of STS overall survival was 0.826. Notably, the splicing events of certain STS key genes were significantly associated with STS 2-year overall survival in the present study, including exon skip (ES) events in MDM2 and EWSR1, alternate terminator events in CDKN2A and HMGA2 for dedifferentiated liposarcoma, ES in MDM2 and alternate promoter events in CDKN2A for leiomyosarcoma, and ES in EWSR1 for undifferentiated pleomorphic sarcoma. Moreover, splicing correlation networks between AS events and splicing factors revealed that almost all of the AS events showed negatively correlations with the expression of splicing factors. CONCLUSION: An in-depth analysis of alternative RNA splicing could provide new insights into the mechanisms of STS oncogenesis and the potential for novel approaches to this type of cancer therapy.


Assuntos
Processamento Alternativo/genética , Genoma Humano , Sarcoma/genética , Diferenciação Celular , Estudos de Coortes , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Estimativa de Kaplan-Meier , Modelos Genéticos , Proteínas de Neoplasias/metabolismo , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
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