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1.
Gene ; 721: 144100, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31493508

RESUMO

BACKGROUND: Breast cancer (BRCA) is the most prevalent cancer that threatens female health. A growing body of evidence has demonstrated the non-negligible effects of messenger RNAs (mRNAs) on biological processes involved in cancers; however, there is no definite conclusion regarding the role of mRNAs in predicting the prognosis of BRCA patients. MATERIALS AND METHODS: We systematically screened the mRNA expression landscape and clinical data of samples from the Cancer Genome Atlas (TCGA). Univariate Cox analysis and robust likelihood-based survival analysis were conducted to identify key mRNAs associated with BRCA. Furthermore, risk scores based on multivariate Cox analysis divided the training set into high-risk and low-risk groups. ROC analysis determined the optimal cut-off point for patient classification of risk levels. The prognostic model was additionally validated in the testing set and complete dataset. Finally, we plotted the survival curves for the mRNAs used in our model. RESULTS: We obtained the original expression data of 13,617 mRNAs from a total of 1088 samples. After comprehensive survival analysis, the four-mRNA (ACSL1, OTUD3, PKD1L2, and WISP1) prognosis risk assessment model was constructed. Furthermore, the area under cure (AUC) was 0.834, indicating that the model was meaningful and reasonable. In each dataset, analysis based on the four-mRNA signature risk score indicated that the survival status of the group with high risk score was worse than that of the group with low risk scores. Patients with strong mRNA expression of OTUD3, PKD1L2, and WISP1 tended to have good prognosis, whereas patients with high ACSL1 expression tended to have poor prognosis. CONCLUSION: In summary, we constructed a four-mRNA prognosis risk assessment model for BRCA. The newly developed model offers more possibilities for assessing prognosis and guiding the selection of better treatment strategies for BRCA.


Assuntos
Neoplasias da Mama , Bases de Dados de Ácidos Nucleicos , Modelos Biológicos , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Proteínas de Sinalização Intercelular CCN/biossíntese , Proteínas de Sinalização Intercelular CCN/genética , Coenzima A Ligases/biossíntese , Coenzima A Ligases/genética , Intervalo Livre de Doença , Feminino , Humanos , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Receptores Acoplados a Proteínas-G/biossíntese , Receptores Acoplados a Proteínas-G/genética , Taxa de Sobrevida , Proteases Específicas de Ubiquitina/biossíntese , Proteases Específicas de Ubiquitina/genética
2.
Hematol Oncol ; 37(4): 375-382, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31408531

RESUMO

In large B-cell lymphoma (LBCL), MYC translocation and MYC/BCL2 or MYC/BCL6 double hit (DH) are associated with poor prognosis, and there is an unmet need for novel treatment targets in this patient group. Treatments targeting the PD-L1/PD-1 pathway are still poorly elucidated in LBCL. PD-L1 expression might predict response to treatment targeting the PD-L1/PD-1 pathway. We therefore investigated the relationship between PD-L1 protein and mRNA expression levels and MYC and DH translocation in LBCL. We detected MYC, BCL2, and BCL6 translocation by fluorescent in situ hybridization in tissue samples from 130 patients randomly selected from two cohorts of patients with LBCL: 49 patients with MYC translocation of whom 36 had DH and 81 without MYC translocation. PD-L1 protein expression was detected by immunohistochemistry (IHC) in tissue samples from 77 patients and PD-L1 mRNA expression by next-generation RNA sequencing (NGS) in another 77 patients. Twenty-four patients overlapped, ie, were analysed with both IHC and NGS. Nonparametric tests were performed to evaluate intergroup differences. PD-L1 protein expression level was significantly lower in patients with MYC (n = 42, median = 3.3%, interquartile range [IQR] 0.0-10.8) or DH translocations (n = 31, median = 3.3%, IQR 0.0-10.0) compared with patients with no MYC (n = 35, median = 16.7%, IQR 3.3-30.0) or no DH translocations (n = 46, 13.3%, IQR 2.5-30.0), P = .004 and P ≤ .001, respectively. PD-L1 mRNA expression was also significantly lower in patients with MYC or DH translocations, P = .001 and P = .006, respectively. Higher PD-L1 protein and mRNA expression levels were associated with non-germinal centre (GC) type compared with germinal centre B-cell (GCB)-type diffuse LBCL (DLBCL), P = .004 and P = .002, respectively. In conclusion, we report an association between low PD-L1 expression and MYC and DH translocation in patients with LBCL. Our findings may indicate that patients with MYC or DH translocation may benefit less from treatment with PD-L1/PD-1-inhibitors compared with patients without these translocations. This should be evaluated in larger, prospective, consecutive trials.


Assuntos
Antígeno B7-H1/biossíntese , Regulação Neoplásica da Expressão Gênica , Genes myc , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas de Neoplasias/biossíntese , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Translocação Genética , Adulto , Idoso , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Antígeno B7-H1/genética , Feminino , Perfilação da Expressão Gênica , Genes bcl-2 , Centro Germinativo/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-bcl-6/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Estudos Retrospectivos
3.
Hematol Oncol ; 37(4): 474-482, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325181

RESUMO

LncRNAs play critical roles in various pathophysiological and biological processes, such as protein translation, RNA splicing, and epigenetic modification. Indeed, abundant evidences demonstrated that lncRNA act as competing endogenous RNAs (ceRNAs) to participate in tumorigenesis. However, little is known about the underlying function of lncRNA in nonhomologous end joining (NHEJ) pathway 1 (LINP1) in pediatric and adolescent acute myeloid leukemia (AML). The expression of LINP1 was examined in AML patient samples by qRT-PCR. Cell proliferation was examined by CCK-8 and Edu assays. ß-Galactosidase senescence assay, mGlucose uptake assay, lactate production assay, and Gene Ontology (GO) analysis were performed for functional analysis. We found that LINP1 was significantly overexpressed in AML patients at diagnosis, whereas downregulated after complete remission (CR). Furthermore, knockdown of LINP1 expression remarkably suppressed glucose uptake and AML cell maintenance. Mechanistically, LINP1 was found to inhibit the glucose metabolism by suppressing the expression of HNF4a. Both LINP1 and HNF4a knockdown reduced the expression levels of AMPK phosphorylation and WNT5A, indicating for the first time that LINP1 strengthened the HNF4a-AMPK/WNT5A signaling pathway involved in cell glucose metabolism modulation and AML cell survival. Taken together, our results indicated that LINP1 promotes the malignant phenotype of AML cells and stimulates glucose metabolism, which can be regarded as a potential prognostic marker and therapeutic target for AML.


Assuntos
Adenilato Quinase/fisiologia , Fator 4 Nuclear de Hepatócito/fisiologia , Leucemia Mieloide Aguda/genética , RNA Longo não Codificante/fisiologia , RNA Neoplásico/fisiologia , Transdução de Sinais/fisiologia , Proteína Wnt-5a/fisiologia , Adolescente , Animais , Medula Óssea/patologia , Divisão Celular , Criança , Regulação Leucêmica da Expressão Gênica , Técnicas de Silenciamento de Genes , Ontologia Genética , Glucose/metabolismo , Fator 4 Nuclear de Hepatócito/biossíntese , Fator 4 Nuclear de Hepatócito/genética , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Púrpura Trombocitopênica Idiopática/metabolismo , Interferência de RNA , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , Distribuição Aleatória , Indução de Remissão , Transdução de Sinais/genética , Células THP-1
4.
Cell Physiol Biochem ; 53(1): 258-280, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31313541

RESUMO

BACKGROUND/AIMS: Although neuroblastoma is a heterogeneous cancer, a substantial portion overexpresses CD71 (transferrin receptor 1) and MYCN. This study provides a mechanistically driven rationale for a combination therapy targeting neuroblastomas that doubly overexpress or have amplified CD71 and MYCN. For this subset, CD71 was targeted by its natural ligand, gambogic acid (GA), and MYCN was targeted with an HDAC inhibitor, vorinostat. A combination of GA and vorinostat was then tested for efficacy in cancer and non-cancer cells. METHODS: Microarray analysis of cohorts of neuroblastoma patients indicated a subset of neuroblastomas overexpressing both CD71 and MYCN. The viability with proliferation changes were measured by MTT and colony formation assays in neuroblastoma cells. Transfection with CD71 or MYCN along with quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect expression changes. For pathway analysis, gene ontology (GO) and Protein-protein interaction analyses were performed to evaluate the potential mechanisms of GA and vorinostat in treated cells. RESULTS: For both GA and vorinostat, their pathways were explored for specificity and dependence on their targets for efficacy. For GA-treated cells, the viability/proliferation loss due to GA was dependent on the expression of CD71 and involved activation of caspase-3 and degradation of EGFR. It relied on the JNK-IRE1-mTORC1 pathway. The drug vorinostat also reduced cell viability/proliferation in the treated cells and this was dependent on the presence of MYCN as MYCN siRNA transfection led to a blunting of vorinostat efficacy and conversely, MYCN overexpression improved the vorinostat potency in those cells. Vorinostat inhibition of MYCN led to an increase of the pro-apoptotic miR183 levels and this, in turn, reduced the viability/proliferation of these cells. The combination treatment with GA and vorinostat synergistically reduced cell survival in the MYCN and CD71 overexpressing tumor cells. The same treatment had no effect or minimal effect on HEK293 and HEF cells used as models of non-cancer cells. CONCLUSION: A combination therapy with GA and vorinostat may be suitable for MYCN and CD71 overexpressing neuroblastomas.


Assuntos
Antígenos CD , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sistemas de Liberação de Medicamentos , Proteína Proto-Oncogênica N-Myc , Neuroblastoma , Receptores da Transferrina , Antígenos CD/genética , Antígenos CD/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Células HEK293 , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Proteína Proto-Oncogênica N-Myc/antagonistas & inibidores , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Receptores da Transferrina/antagonistas & inibidores , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo , Vorinostat/farmacologia , Xantonas/farmacologia
5.
Gene ; 715: 144012, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31357021

RESUMO

Long noncoding RNAs (lncRNAs) have been shown to play an important role in tumor biogenesis and prognosis. The glioma is a grade classified cancer, however, we still lack the knowledge on their function during glioma progression. While previous studies have shown how lncRNAs regulate protein-coding gene epigenetically, it is still unclear how lncRNAs are regulated epigenetically. In this study, we firstly analyzed the RNA-seq data systematically across grades II, IV, and IV of glioma samples. We identified 60 lncRNAs that are significantly differentially expressed over disease progression (DElncRNA), including well-known PVT1, HOTAIR, H19 and rarely studied CARD8-AS, MIR4435-2HG. Secondly, by integrating HM450K methylation microarray data, we demonstrated that some of the lncRNAs are epigenetically regulated by methylation. Thirdly, we developed a DESeq2-GSEA-ceRNA-survival analysis strategy to investigate their functions. Particularly, MIR4435-2HG is highly expressed in high-grade glioma and may have an impact on EMT and TNFα signaling pathway by functioning as a miRNA sponge of miR-125a-5p and miR-125b-5p to increase the expression of CD44. Our results revealed the dynamic expression of lncRNAs in glioma progression and their epigenetic regulation mechanism.


Assuntos
Metilação de DNA , DNA de Neoplasias , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Glioma , MicroRNAs , RNA Longo não Codificante , RNA Neoplásico , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Perfilação da Expressão Gênica , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética
6.
Hematology ; 24(1): 487-491, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31210592

RESUMO

OBJECTIVES: Acute myeloid leukemia (AML) is a heterogeneous and highly recurrent hematological malignancy. Studies have shown an association between microRNAs and drive genes in AMLs. However, the regulatory roles of miRNAs in AML and how they act on downstream targets and the signaling pathway has been little studied. METHODS: As to understand the mechanism of mRNA-miRNA interaction in the blood malignancy from a large scale of transcriptomic sequencing studies, we applied a comprehensive miRNA-mRNA association, co-expression gene network and ingenuity pathway analysis using TCGA AML datasets. RESULTS: Our results showed that his-mir-335 was a critical regulatory of homeobox A gene family. PBX3, KAT6A, MEIS1, and COMMD3-BMI1 were predicted as top transcription regulators in the regulatory network of the HOXA family. The most significantly enriched functions were cell growth, proliferation, and survival in the mRNA-miRNA network. CONCLUSION: Our work revealed that regulation of the HOXA gene family and its regulation played an important role in the development of AML.


Assuntos
Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes , Leucemia Mieloide Aguda , MicroRNAs , RNA Mensageiro , RNA Neoplásico , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , MicroRNAs/biossíntese , MicroRNAs/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética
7.
Int J Mol Med ; 44(1): 135-144, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115495

RESUMO

Recently, the use of low­intensity ultrasound (LIUS) combined with chemotherapeutic agents is widely used in clinical practice, mainly for the treatment of cancer; however, the mechanisms as to how LIUS enhances the antitumor effects of these agents are not fully understood. The aim of the present study was to explore the synergistic antitumor effects and mechanisms of cisplatin (DDP) combined with LIUS (LIUS­DDP) in hepatocellular carcinoma (HCC). We reported that LIUS effectively enhanced Huh7 and HCCLM3 cell sensitivity to a low concentration of DDP. Reverse transcription­quantitative polymerase chain reaction analysis revealed that LIUS could increase the expression of microRNA­34a (miR­34a) in HCC cells following DDP treatment. In addition, LIUS­DDP significantly increased intracellular reactive oxygen species (ROS) levels in vitro, and the upregulation of miR­34a induced by LIUS­DDP was reversed by the ROS scavenger N­acetylcysteine, suggesting that LIUS upregulates the expression of miR­34a via production of ROS. In addition, knockdown of miR­34a in HCC cells significantly suppressed the synergistic effects of LIUS­DDP treatment. Conversely, overexpression of miR­34a enhanced these synergistic effects. The results of a dual­luciferase assay indicated that c­Met, a well­known oncogene, was a target of miR­34a. We also determined that LIUS­DDP treatment inhibited the expression of c­Met, possibly due to increased ROS production, which upregulated miR­34a expression. Furthermore, overexpression of c­Met reversed the synergistic effects of LIUS­DDP treatment. Our findings suggest that LIUS could enhance the chemosensitivity of HCC cells to DDP by altering the miR­34a/c­Met axis. Therefore, DDP combined with LIUS may be a potential therapeutic application for the clinical treatment of patients with HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , MicroRNAs/biossíntese , Proteínas Proto-Oncogênicas c-met/metabolismo , RNA Neoplásico/biossíntese , Ondas Ultrassônicas , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Espécies Reativas de Oxigênio/metabolismo
8.
Hematol Oncol ; 37(4): 409-417, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31102419

RESUMO

Accumulating studies have focused on circulating microRNAs, which might be potential biomarkers for different malignancies. The aim of this study was to investigate the potential of serum exosomal microRNAs to be novel serum biomarkers for smouldering myeloma (SMM) or even multiple myeloma (MM). The levels of serum exosomal microRNAs and serum circulating microRNAs were measured in healthy individuals and patients with SMM (n = 20) or MM (n = 20). Serum exosomal microRNAs and serum circulating microRNAs were extracted from serum, and the expression levels of selected microRNAs were quantified by real-time polymerase chain reaction (PCR). The levels of serum exosome-derived miR-20a-5p, miR-103a-3p, and miR-4505 were significantly different among patients with MM, patients with SMM, and healthy individuals, while there were differences in the levels of let-7c-5p, miR-185-5p, and miR-4741 in patients with MM relative to those in SMM patients or healthy controls. Additionally, a significant correlation was rarely found between the levels of serum and exosomal microRNAs. This study shows that serum exosomal microRNAs can be used independently as novel serum biomarkers for MM.


Assuntos
Exossomos/química , MicroRNAs/sangue , Mieloma Múltiplo/sangue , RNA Neoplásico/sangue , Adulto , Idoso , Doenças Assintomáticas , Biomarcadores Tumorais/sangue , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , MicroRNAs/biossíntese , MicroRNAs/genética , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/sangue , RNA Neoplásico/biossíntese , RNA Neoplásico/genética
9.
Biomed Res Int ; 2019: 2063823, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061821

RESUMO

Background: Although several studies have proved the relationship between the prognostic value of miRNA-15a and different types of cancer, the result remains controversial. Thus, a meta-analysis was conducted to clarify the prognostic value of miRNA-15a expression level in human cancers. Methods: We enrolled appropriate literature by searching the databases of PubMed, Embase, and Web of Science. Subsequently, we extracted HRs and their 95% CIs and calculated pooled results of miRNA-15a for overall survival (OS) and disease-free survival (DFS). Besides, subgroup analysis, sensitivity analysis, and publication bias were also revealed in this study. We also further validated this meta-analysis using the Kaplan-Meier plotter database. Result: 10 studies, including 1616 patients, were embraced in our meta-analysis. The result showed the lower expression of miRNA-15a significantly predicted adverse OS (HR=2.17, 95% CI: 1.41-3.34), but there is no significant association between the expressing level and DFS in cancer patient (HR=2.04, 95% CI: 0.60-6.88). Based on Kaplan-Meier plotter database, we found the same results in bladder Carcinoma, head-neck squamous cell carcinoma, liver hepatocellular carcinoma, lung squamous cell carcinoma, pancreatic ductal adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma, but opposite results were found in cervical squamous cell carcinoma and esophageal carcinoma. Conclusion: Low expressing levels of miRNA-15a indicated poor OS, while miRNA-15a can be used as a prediction biomarker in different cancer types.


Assuntos
Biomarcadores Tumorais/biossíntese , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Neoplasias/metabolismo , Neoplasias/mortalidade , RNA Neoplásico/biossíntese , Biomarcadores Tumorais/genética , Intervalo Livre de Doença , Humanos , MicroRNAs , Neoplasias/genética , Neoplasias/patologia , Valor Preditivo dos Testes , RNA Neoplásico/genética , Taxa de Sobrevida
10.
Biomed Res Int ; 2019: 5437531, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949502

RESUMO

Glioma is a lethal, malignant intracranial tumor that becomes progressively common. It has been shown that long noncoding RNAs (lncRNAs) serve important roles in numerous diseases such as gliomas. lncRNAs can regulate the expression of targeted genes through various mechanisms. To identify a novel lncRNA that may be critical in glioma, the present study downloaded the RNA expression profiles of 171 glioma tissues and 5 normal tissues from The Cancer Genome Atlas (TCGA) database using the TCGAbiolinks package in R. Then, lncRNAs in the downloaded TCGA data were identified using the HUGO Gene Nomenclature Committee (HGNC). Based on the fragments per kilobase million value, differential expression analysis was conducted using the limma package in R. In addition, receiver operating characteristic (ROC) analysis was performed, and the area under the curve (AUC) was evaluated using the ROCR package in R. A total of 178 lncRNAs corresponding to differentially expressed genes with an AUC >0.85 were selected. Upon identifying the differential lncRNAs, ceRNA networks were constructed with these differential lncRNAs using the starbase database. From these networks, the top 10% hub genes were selected. In addition, the present study randomly selected 4 lncRNAs for quantitative polymerase chain reaction validation in tissue samples. The results revealed that lncRNA ASB16-AS1 exhibited significantly differential expression in tissue samples and was significantly associated with tumor staging and grading. Furthermore, the proliferation, invasion, and migration of U87MG and U251 glioblastoma stem-like cells (U87GS, U251GS) were significantly inhibited upon inhibition of ASB16-AS1, and the expression of key proteins in the EMT signaling pathway was affected by knocking down ASB16-AS1. Overall, the present study revealed that lncRNA ASB16-AS1 improves the proliferation, migration, and invasion of glioma cells.


Assuntos
Neoplasias Encefálicas/metabolismo , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Feminino , Glioma/genética , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , RNA Longo não Codificante/genética , RNA Neoplásico/genética , Transdução de Sinais/genética
11.
Biomed Res Int ; 2019: 4897905, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30993113

RESUMO

Osteosarcoma (OS) is one of the most common primary malignant bone tumors in adolescents with a high mortality rate. MicroRNA (miRNA) is a kind of noncoding RNAs and has been proved to participate in many physiological processes. Many miRNAs have been reported to act as function regulators in OS. In our study, the miRNA and gene expression profiles of OS were downloaded from GEO Datasets and the differential expression analysis was performed using GEO2R. 58 up- and 126 downregulated miRNAs were found. In the three OS gene profiles, 125 up- and 27 downregulated genes were found to be differentially expressed in at least two profiles. The miRNA-mRNA networks were constructed to predict the potential target genes of 10 most up- and downregulated miRNA. Venn analysis was used to detect the coexpressed differentially expressed genes (DEGs). EBF2, one of the upregulated DEGs, was also a potential target gene of miR-182-3p. Knockdown and overexpression of miR-182-3p resulted in overexpression and downexpression of EBF2 separately. Luciferase reporter gene experiment further verified the binding site of miR-182-3p and EBF2. CCK8 assay showed that miR-182-3p knockdown can further enhance the proliferation activity of OS cells, while overexpressing miR-182-3p can inhibit the proliferation activity of OS cells. Our research indicated that downexpression of miR-182-3p in OS cells results in overexpression of EBF2 and promotes the progression of OS.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Neoplasias Ósseas/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/biossíntese , Proteínas de Neoplasias/biossíntese , Osteossarcoma/metabolismo , RNA Neoplásico/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , MicroRNAs/genética , Proteínas de Neoplasias/genética , Osteossarcoma/genética , Osteossarcoma/patologia , RNA Neoplásico/genética
12.
Mol Cell Biochem ; 457(1-2): 93-103, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30993496

RESUMO

Metastasis accounts for the majority of cancer-associated mortality and renders the targeted therapy fruitless in the patients of breast cancer. Matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF-C) are thought to be involved in tumor progression and metastasis. The aim of this study was to investigate the expression of MMP-9 and VEGF-C at both mRNA and protein levels in breast cancer and to correlate with lymph node metastasis and other clinicopathological characteristics. Biopsy specimens (N = 100) of breast cancer & benign breast disease (N = 100) were investigated for the mRNA expression of MMP-9 and VEGF-C by Real-time PCR and Protein expression by Western blot. Elevated levels of MMP-9 (p < 0.001) and VEGF-C (p < 0.001) expression were detected in breast cancer with corresponding to benign breast disease. Additionally, we found significantly increased levels of MMP-9 and VEGF-C in node-positive group with respect to node-negative group. Moreover, the levels of MMP-9 were significantly increased in larger tumor size (T3/T4) (p < 0.05) as compared to smaller size (T1/T2), which suggests that MMP-9 plays an important role in the progression of breast cancer. VEGF-C expression was associated with the TNM stage of tumor (p < 0.05). Further, a significant positive correlation was established between the mRNA levels of these two genes (p < 0.001). However, we could not obtain any significant correlation between expression of these genes with other clinicopathological parameters like tumor grade, age, menopausal status, and receptor status like ER, PR, and Her2. This study suggests that the high expression of MMP-9 and VEGF-C could act as markers for the tumor presence in breast cancer. In addition, this study recommends that expression of MMP-9 and VEGF-C was significantly associated with lymph node status and may provide valuable diagnosis of lymph node metastasis in breast cancer patients. Further, MMP-9 expression was associated with the tumor size and VEGF-C expression was correlated with the staging of the tumor, although no association was observed with other clinicopathological variables.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 9 da Matriz , Proteínas de Neoplasias , Fator C de Crescimento do Endotélio Vascular , Adulto , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Índia , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/genética , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Fator C de Crescimento do Endotélio Vascular/biossíntese , Fator C de Crescimento do Endotélio Vascular/genética
13.
Med Sci Monit ; 25: 3041-3060, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31020952

RESUMO

BACKGROUND Bladder cancer is a multifactorial disease with increasing incidence and mortality. Genetic alterations and altered expressions of mRNAs, long non-coding RNAs (lncRNAs), and miRNAs have been shown to play important roles in the tumorigenesis of bladder cancer. However, the functions of key RNAs and their regulatory network in bladder cancer are still to be elucidated. MATERIAL AND METHODS RNA profiles were downloaded from The Cancer Genome Atlas (TCGA) database. The differentially expressed mRNAs, lncRNAs, and miRNAs in bladder cancer were acquired through analyses of data from 414 bladder cancer tissues and 19 normal bladder tissues. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis was performed by using "DAVID6.8" and the R package "ClusterProfile". Protein-protein interaction and competing endogenous RNA (ceRNA) networks were constructed by using "STRING" database and Cytoscape 3.6.2. Based on the clinical data and Cox regression, a prognosis model was established, and survival analysis was performed. RESULTS A total of 1819 mRNAs, 659 lncRNAs, and 160 miRNAs were identified as significantly differentially expressed in bladder cancer of which 52 mRNAs, 58 lncRNAs, and 22 miRNAs were incorporated in the ceRNA network. CFL2 and TPM2 were found to be downregulated and showed significant correlation to each other in bladder cancer. HOXB5 and 6 lncRNAs (ADAMTS9-AS1, AC112721.1, LINC00460, AC110491.1, LINC00163, and HCG22) were strongly associated with high-grade, disease stages, and overall survival. CONCLUSIONS In this study, we have identified differentially expressed mRNAs, lncRNAs, and miRNAs in bladder cancer which were strongly associated with oncogenesis and prognosis. Further experimental studies are necessary to validate these results.


Assuntos
RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Neoplasias da Bexiga Urinária/genética , Bases de Dados Genéticas , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Estimativa de Kaplan-Meier , MicroRNAs/genética , Prognóstico , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , Análise de Sobrevida , Neoplasias da Bexiga Urinária/metabolismo
14.
Biomed Res Int ; 2019: 3526407, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31019967

RESUMO

Background: Cholangiocarcinoma (CCA) is the second most common malignant primary liver tumor and has shown an alarming increase in incidence over the last two decades. However, the mechanisms behind tumorigenesis and progression remain insufficient. The present study aimed to uncover the underlying regulatory mechanism on CCA and find novel biomarkers for the disease prognosis. Method: The RNA-sequencing (RNA-seq) datasets of lncRNAs, miRNAs, and mRNAs in CCA as well as relevant clinical information were obtained from the Cancer Genome Atlas (TCGA) database. After pretreatment, differentially expressed RNAs (DERNAs) were identified and further interrogated for their correlations with clinical information. Prognostic RNAs were selected using univariate Cox regression. Then, a ceRNA network was constructed based on these RNAs. Results: We identified a total of five prognostic DEmiRNAs, 63 DElncRNAs, and 90 DEmRNAs between CCA and matched normal tissues. Integrating the relationship between the different types of RNAs, an lncRNA-miRNA-mRNA network was established and included 28 molecules and 47 interactions. Screened prognostic RNAs involved in the ceRNA network included 3 miRNAs (hsa-mir-1295b, hsa-mir-33b, and hsa-mir-6715a), 7 lncRNAs (ENSG00000271133, ENSG00000233834, ENSG00000276791, ENSG00000241155, COL18A1-AS1, ENSG00000274737, and ENSG00000235052), and 18 mRNAs (ANO9, FUT4, MLLT3, ABCA3, FSCN2, GRID2IP, NCK2, MACC1, SLC35E4, ST14, SH2D3A, MOB3B, ACTL10, RAB36, ATP1B3, MST1R, SEMA6A, and SEL1L3). Conclusions: Our study identified novel prognostic makers and predicted a previously unknown ceRNA regulatory network in CCA and may provide novel insight into a further understanding of lncRNA-mediated ceRNA regulatory mechanisms in CCA.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Neoplasias Hepáticas , MicroRNAs , RNA Longo não Codificante , RNA Mensageiro , RNA Neoplásico , Idoso , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , MicroRNAs/biossíntese , MicroRNAs/genética , Pessoa de Meia-Idade , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Análise de Sequência de RNA , Taxa de Sobrevida
15.
Gene ; 701: 23-31, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30898713

RESUMO

As a tumor metastasis suppressor gene, LASS2 has been found to be negatively associated with the stage of bladder cancer and overall survival of patients. However, the mechanisms regulating LASS2 in bladder cancer remain poorly understood. Here, we aim to identify a miRNA that targets LASS2 from bladder cancer-associated miRNAs and to reveal its potential functions in bladder cancer cells. Through miRNA microarray and bioinformatics analyses, we identified miR-3622a as a negative regulator of LASS2. The expression levels of miR-3622a in bladder cancer tissues were negatively correlated with the overall survival of patients. Overexpression of miR-3622a significantly increased the proliferation and invasion abilities of bladder cancer cells. In conclusion, our results indicate that miR-3622a promotes the proliferation and invasion of bladder cancer cells by downregulating LASS2.


Assuntos
Proliferação de Células , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/biossíntese , MicroRNAs/biossíntese , RNA Neoplásico/biossíntese , Esfingosina N-Aciltransferase/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Neoplasias da Bexiga Urinária/metabolismo , Linhagem Celular Tumoral , Humanos , Proteínas de Membrana/genética , MicroRNAs/genética , Invasividade Neoplásica , RNA Neoplásico/genética , Esfingosina N-Aciltransferase/genética , Proteínas Supressoras de Tumor/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
16.
Gene ; 701: 41-45, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30902790

RESUMO

BACKGROUND: There is significant controversy in the literature regarding the relationship between hypoxia and salivary gland neoplasms (SGNs). OBJECTIVE: The current study aims to investigate levels of hypoxia markers in both benign and malignant salivary neoplasms. PATIENTS AND METHODS: The current study sample is comprised of a total of 62 samples. HIF-1α expression was evaluated by immunohistochemistry. Additionally, HIF-1α mRNA and miR-210 levels were assessed using qRT-PCR. RESULTS: No differences in HIF-1α expression were observed among the control group, benign and malignant SGNs. Similarly, HIF-1α mRNA levels were similar between benign and malignant SGNs. Also, there was no difference in miR-210 expression between case and control groups. CONCLUSION: The angiogenic markers, miR-210 and HIF-1α, do not appear to distinguish malignancy in salivary glands.


Assuntos
Biomarcadores Tumorais/biossíntese , Regulação Neoplásica da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Proteínas de Neoplasias/biossíntese , Neovascularização Patológica/metabolismo , Neoplasias das Glândulas Salivares , Estudos Transversais , Feminino , Humanos , Masculino , MicroRNAs/biossíntese , Neovascularização Patológica/patologia , RNA Neoplásico/biossíntese , Estudos Retrospectivos , Neoplasias das Glândulas Salivares/irrigação sanguínea , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/patologia
17.
J Biol Chem ; 294(15): 6172-6187, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30718276

RESUMO

Yin Yang 1 (YY1) is a zinc-finger protein that plays critical roles in various biological processes by interacting with DNA and numerous protein partners. YY1 has been reported to play dual biological functions as either an oncogene or tumor suppressor in the development and progression of multiple cancers, but its role in human nasopharyngeal carcinoma (NPC) has not yet been revealed. In this study, we found that YY1 overexpression significantly inhibits cell proliferation and cell-cycle progression from G1 to S and promotes apoptosis in NPC cells. Moreover, we identified YY1 as a component of the c-Myc complex and observed that ectopic expression of YY1 inhibits c-Myc transcriptional activity, as well as the promoter activity and expression of the c-Myc target gene microRNA-141 (miR-141). Furthermore, restoring miR-141 expression could at least partially reverse the inhibitory effect of YY1 on cell proliferation and tumor growth and on the expression of some critical c-Myc targets, such as PTEN/AKT pathway components both in vitro and in vivo We also found that YY1 expression is reduced in NPC tissues, negatively correlates with miR-141 expression and clinical stages in NPC patients, and positively correlates with survival prognosis. Our results reveal a previously unappreciated mechanism in which the YY1/c-Myc/miR-141 axis plays a critical role in NPC progression and may provide some potential and valuable targets for the diagnosis and treatment of NPC.


Assuntos
MicroRNAs/biossíntese , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Neoplásico/biossíntese , Transcrição Genética , Proteínas Supressoras de Tumor/metabolismo , Fator de Transcrição YY1/metabolismo , Adulto , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Proteínas Proto-Oncogênicas c-myc/genética , RNA Neoplásico/genética , Proteínas Supressoras de Tumor/genética , Fator de Transcrição YY1/genética
18.
Cell Biochem Funct ; 37(2): 84-92, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30773676

RESUMO

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death over the world. It is well studied that long noncoding RNA colon cancer-associated transcript-1 (CCAT1) played important roles in variety of cancers promoting cell proliferation and metastasis by acting as a competing endogenous RNA (ceRNA) of microRNAs. However, whether CCAT1 could regulate HCC by serving as a ceRNA of microRNA remains to be revealed. In this study, we demonstrated that CCAT1 was highly expressed in HCC tissues and remarkably associated with metastasis. With a bioinformatics prediction and functional assay validation, we found a binding site of miR-30c-2-3p on CCAT1, which was important for CCAT1 to promote cell proliferation. Interestingly, we further revealed a novel recognition site for miR-30c-2-3p on the 3'UTR of CCNE1 by mutative method, luciferase assay, and cell viability confirmation. In general, CCAT1 regulate the expression of CCNE1 by acting as a ceRNA to sponge miR-30c-2-3p in regulating the cell proliferation of HCC. These results suggest that CCAT1 may be a new therapy target for HCC in the future. SIGNIFICANCE OF THE STUDY: Our findings may broaden the understanding of the role of CCAT1 in tumorigenesis and may provide a new therapy target for HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/metabolismo , MicroRNAs/biossíntese , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Regulação para Cima , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Neoplásico/genética
19.
Biochem Cell Biol ; 97(2): 91-99, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30681889

RESUMO

This study investigated the role and action of the Salvador 1 protein (SAV1, also called WW45) in colorectal cancer (CRC). For this, CRC SW480 and HCT116 cells were infected with lentiviruses of SAV1 overexpression vector (lenti-SAV1) and SAV1 short hairpin RNA (sh-SAV1) to overexpress and silence SAV1 respectively, or transfected with microRNA-21 (miR-21) mimic to overexpress miR-21. Relative mRNA levels of SAV1 and relative miR-21 levels in CRC tissues or cells were detected. The effects of SAV1 and miR-21 on cell proliferation and apoptosis were evaluated using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and annexin V - fluorescein isothiocyanate (FITC) - propidium iodide (PI) flow cytometry, respectively. Our results revealed that SAV1 was downregulated in CRC tissues compared with the adjacent noncancerous tissues. Furthermore, SAV1 overexpression inhibited proliferation and promoted apoptosis in SW480 and HCT116 cells, whereas knockdown of SAV1 exerted the opposite effect. Additionally, the tumorigenesis of SW480 cells in xenografted mice was significantly inhibited by SAV1 overexpression but promoted by SAV1 knockdown. MiR-21 levels significantly and negatively correlated with SAV1 expression in CRC tissues. More importantly, miR-21 overexpression significantly abolished the SAV1-mediated inhibition of proliferation and stimulation of apoptosis of SW480. In conclusion, SAV1 suppresses tumor growth in CRC and is regulated by miR-21.


Assuntos
Apoptose , Proteínas de Ciclo Celular/biossíntese , Proliferação de Células , Neoplasias Colorretais/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/biossíntese , Proteínas de Neoplasias/biossíntese , RNA Neoplásico/biossíntese , Proteínas de Ciclo Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Técnicas de Silenciamento de Genes , Células HCT116 , Humanos , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA Neoplásico/genética
20.
J Biol Chem ; 294(13): 4854-4866, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30674552

RESUMO

Epstein-Barr virus-associated gastric cancer (EBVaGC) accounts for about 10% of all gastric cancer cases and has unique pathological and molecular characteristics. EBV encodes a large number of microRNAs, which actively participate in the development of EBV-related tumors. Here, we report that EBV-miR-BART3-3p (BART3-3p) promotes gastric cancer cell growth in vitro and in vivo Moreover, BART3-3p inhibits the senescence of gastric cancer cells induced by an oncogene (RASG12V) or chemotherapy (irinotecan). LMP1 and EBNA3C encoded by EBV have also been reported to have antisenescence effects; however, in EBVaGC specimens, LMP1 expression is very low, and EBNA3C is not expressed. BART3-3p inhibits senescence of gastric cancer cells in a nude mouse model and inhibits the infiltration of natural killer cells and macrophages in tumor by altering the senescence-associated secretory phenotype (SASP). Mechanistically, BART3-3p directly targeted the tumor suppressor gene TP53 and caused down-regulation of p53's downstream target, p21. Analysis from clinical EBVaGC samples also showed a negative correlation between BART3-3p and TP53 expression. It is well known that mutant oncogene RASG12V or chemotherapeutic drugs can induce senescence, and here we show that both RASG12V and a chemotherapy drug also can induce BART3-3p expression in EBV-positive gastric cancer cells, forming a feedback loop that keeps the EBVaGC senescence at a low level. Our results suggest that, although TP53 is seldom mutated in EBVaGC, its expression is finely regulated such that EBV-encoded BART3-3p may play an important role by inhibiting the senescence of gastric cancer cells.


Assuntos
Carcinogênese/metabolismo , Senescência Celular , Regulação Neoplásica da Expressão Gênica , Regulação Viral da Expressão Gênica , Herpesvirus Humano 4/metabolismo , MicroRNAs/biossíntese , RNA Neoplásico/biossíntese , RNA Viral/biossíntese , Neoplasias Gástricas/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Herpesvirus Humano 4/genética , Humanos , MicroRNAs/genética , RNA Neoplásico/genética , RNA Viral/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/virologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/metabolismo
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