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1.
Mol Ther Nucleic Acids ; 18: 476-484, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31670197

RESUMO

Cytogenetically normal acute myeloid leukemia (CN-AML) presents with diverse outcomes in different patients and is categorized as an intermediate prognosis group. It is important to identify prognostic factors for CN-AML risk stratification. In this study, using the TCGA CN-AML dataset, we found that the scavenger receptor stabilin-1 (STAB1) is a prognostic factor for poor outcomes and validated it in three other independent CN-AML datasets. The high STAB1 expression (STAB1high) group had shorter event-free survival compared with the low STAB1 expression (STAB1low) group in both the TCGA dataset (n = 79; p = 0.0478) and GEO: GSE6891 dataset (n = 187; p = 0.0354). Differential expression analysis between the STAB1high and STAB1low groups revealed that upregulated genes in the STAB1high group were enriched in pathways related to cell adhesion and migration and immune responses. We confirmed that STAB1 suppression inhibits cell growth in KG1a and NB4 leukemia cells. Expression correlation analyses between STAB1 and cancer drug targets suggested that patients in the STAB1low group are more sensitive to the BCL2 inhibitor venetoclax, and we confirmed it in cell lines. In conclusion, we identified STAB1 as a prognostic factor for CN-AML in multiple datasets, explored its underlying mechanism, and provided potential therapeutic indications.

2.
J Immunol Res ; 2019: 4080735, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428656

RESUMO

Rheumatoid arthritis (RA) and osteoarthritis (OA) are common rheumatic disorders that primarily involve joints. The inflammation of the synovium can be observed in both of the two diseases. Synovial fibroblasts (SFs) play an important role in the inflammatory process of the synovium. The functional states of synovial fibroblasts are heterogeneous, and the detailed transition process of their functional states is still unclear. By using transcriptomic data of SFs at a single-cell level, we found a similar transition process for SFs in RA and OA. We also identified the potential regulatory effects of the WNT signaling pathway, the TGF-ß signaling pathway, the FcεRI signaling pathway, and the ERBB signaling pathway on modifying the SFs' functional state. These findings indicate potentially overlapped pathogenic mechanisms in these two diseases, which may help uncover new therapeutic targets to ameliorate disease progression.

3.
J Transl Med ; 17(1): 191, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171000

RESUMO

BACKGROUND: Elevated protein expressions of CD markers such as IL2RA/CD25, CXCR4/CD184, CD34 and CD56 are associated with adverse prognosis in acute myeloid leukemia (AML). However, the prognostic value of mRNA expressions of these CD markers in AML remains unclear. Through our pilot evaluation, IL2RA mRNA expression appeared to be the best candidate as a prognostic biomarker. Therefore, the aim of this study is to characterize the prognostic value of IL2RA mRNA expression and evaluate its potential to refine prognostification in AML. METHODS: In a cohort of 239 newly diagnosed AML patients, IL2RA mRNA expression were measured by TaqMan realtime quantitative PCR. Morphological, cytogenetics and mutational analyses were also performed. In an intermediate-risk AML cohort with 66 patients, the mRNA expression of prognostic biomarkers (BAALC, CDKN1B, ERG, MECOM/EVI1, FLT3, ID1, IL2RA, MN1 and WT1) were quantified by NanoString technology. A TCGA cohort was analyzed to validate the prognostic value of IL2RA. For statistical analysis, Mann-Whitney U test, Fisher exact test, logistic regression, Kaplan-Meier and Cox regression analyses were used. RESULTS: In AML cohort of 239 patients, high IL2RA mRNA expression independently predicted shorter relapse free survival (RFS, p < 0.001) and overall survival (OS, p < 0.001) irrespective of age, cytogenetics, FLT3-ITD or c-KIT D816V mutational status. In core binding factor (CBF) AML, high IL2RA mRNA expression correlated with FLT3-ITD status (p = 0.023). Multivariable analyses revealed that high IL2RA expression (p = 0.002), along with c-KIT D816V status (p = 0.013) significantly predicted shorter RFS, whereas only high IL2RA mRNA expression (p = 0.014) significantly predicted shorter OS in CBF AML. In intermediate-risk AML in which multiple gene expression markers were tested by NanoString, IL2RA significantly correlated with ID1 (p = 0.006), FLT3 (p = 0.007), CDKN1B (p = 0.033) and ERG (p = 0.030) expressions. IL2RA (p < 0.001) and FLT3 (p = 0.008) expressions remained significant in predicting shorter RFS, whereas ERG (p = 0.008) and IL2RA (p = 0.044) remained significant in predicting shorter OS. Similar analyses in TCGA intermediate-risk AML showed the independent prognostic role of IL2RA in predicting event free survival (p < 0.001) and OS (p < 0.001). CONCLUSIONS: High IL2RA mRNA expression is an independent and adverse prognostic factor in AML and specifically stratifies patients to worse prognosis in both CBF and intermediate-risk AML.

4.
Curr Med Sci ; 38(1): 35-42, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30074149

RESUMO

Low-dose cytarabine combined with differentiating or DNA hypomethylating agents, such as vitamin D compounds, is a potential regimen to treat acute myeloid leukemia (AML) patients who are unfit for high-intensity chemotherapy. The present study aimed to determine which subset of AML would be most responsive to low-dose cytarabine with the differentiating agent 1,25-dihydroxyvitamin D3 (1,25-D3). Here, firstly, cBioPortal database was used and we found out that vitamin D receptor (VDR) was highly expressed in acute monocytic leukemia (M5) and high VDR expression was associated with a poor survival of AML patients. Then, we confirmed that 1,25-D3 at clinical available concentration could induce more significant differentiation in acute monocytic leukemia cell lines (U937, MOLM-13, THP-1) and blasts from M5 patients than in non-monocytic cell lines (KGla and K562) and blasts from M2 patient. Finally, it was shown that the combination of 1,25-D3 and low-dose cytarabine further increased the differentiating rate, growth inhibition and G0/G1 arrest, while mild changes were found in the apoptosis in acute monocytic leukemia cell lines. Our study demonstrates that the enhanced response of acute monocytic leukemia cells to low-dose cytarabine by 1,25-D3 might indicate a novel therapeutic direction for patients with acute monocytic leukemia, especially for elderly and frail ones.


Assuntos
24,25-Di-Hidroxivitamina D 3/farmacologia , Antineoplásicos/farmacologia , Citarabina/farmacologia , Leucemia Monocítica Aguda/tratamento farmacológico , Vitaminas/farmacologia , 24,25-Di-Hidroxivitamina D 3/administração & dosagem , 24,25-Di-Hidroxivitamina D 3/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citarabina/administração & dosagem , Citarabina/uso terapêutico , Sinergismo Farmacológico , Humanos , Vitaminas/administração & dosagem , Vitaminas/uso terapêutico
5.
Brief Bioinform ; 19(6): 1325-1336, 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-28981576

RESUMO

Different tissues and diseases have distinct transcriptional profilings with specifically expressed genes (SEGs). So, the identification of SEGs is an important issue in the studies of gene function, biological development, disease mechanism and biomarker discovery. However, few accurate and easy-to-use tools are available for RNA sequencing (RNA-seq) data to detect SEGs. Here, we presented SEGtool, a tool based on fuzzy c-means, Jaccard index and greedy annealing method for SEG detection automatically and self-adaptively ignoring data distribution. Testing result showed that our SEGtool outperforms the existing tools, which was mainly developed for microarray data. By applying SEGtool to Genotype-Tissue Expression (GTEx) human tissue data set, we detected 3181 SEGs with tissue-related functions. Regulatory networks reveal tissue-specific transcription factors regulating many SEGs, such as ETV2 in testis, HNF4A in liver and NEUROD1 in brain. Applied to a case study of single-cell sequencing (SCS) data from embryo cells, we identified many SEGs in specific stages of human embryogenesis. Notably, SEGtool is suitable for RNA-seq data and even SCS data with high specificity and accuracy. An implementation of SEGtool R package is freely available at http://bioinfo.life.hust.edu.cn/SEGtool/.

6.
BMC Cancer ; 17(1): 862, 2017 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-29254483

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the leading cause of cancer mortality. Chemical and virus induction are two major risk factors, however, the potential molecular mechanisms of their differences remain elusive. In this study, to identify the similarities and differences between chemical and virus induced HCC models, we compared the gene expression profiles between DEN and HBx mice models, as well as the differences among tumor, para-tumor and normal tissues. METHODS: We sequenced both gene and microRNA (miRNA) expression for HCC tumor tissues, para-tumor and normal liver tissues from DEN model mice (30-week-old) and downloaded the corresponding microarray expression data of HBx model from GEO database. Then differentially expressed genes (DEGs), miRNAs and transcription factors (TFs) were detected by R packages and performed functional enrichment analysis. To explore the gene regulatory network in HCC models, miRNA and TF regulatory networks were constructed by target prediction. RESULTS: For model comparison, although DEGs between tumor and normal tissues in DEN and HBx models only had a small part of overlapping, they shared common pathways including lipid metabolism, oxidation-reduction process and immune process. For tissue comparisons in each model, genes in oxidation-reduction process were down-regulated in tumor tissues and genes in inflammatory response showed the highest expression level in para-tumor tissues. Genes highly expressed in both tumor and para-tumor tissues in two models mainly participated in immune and inflammatory response. Genes expressed in HBx model were also involved in cell proliferation and cell migration etc. Network analysis revealed that several miRNAs such as miR-381-3p, miR-142a-3p, miR-214-3p and TFs such as Egr1, Atf3 and Klf4 were the core regulators in HCC. CONCLUSIONS: Through the comparative analyses, we found that para-tumor tissue is a highly inflammatory tissue while the tumor tissue is specific with both inflammatory and cancer signaling pathways. The DEN and HBx mice models have different gene expression pattern but shared pathways. This work will help to elucidate the molecular mechanisms underlying different HCC models.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Fatores de Transcrição/genética , Animais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Humanos , Metabolismo dos Lipídeos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Camundongos , Transdução de Sinais
7.
J Huazhong Univ Sci Technolog Med Sci ; 37(2): 179-184, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28397044

RESUMO

Increasing studies have demonstrated that interferon gamma (IFN-γ), which serves as a critical inflammatory cytokine, is essential to induce the immunosuppressive effects of mesenchymal stem cells (MSCs). However, the mechanisms underlying the enhanced immunosuppressive effects of IFN-γ-stimulated MSCs (γMSCs) are not fully understood. MSC-derived microvesicles (MSC-MVs) have been viewed as potential pivotal mediators of the immunosuppressive effects of MSCs. Moreover, microRNAs (miRNAs) are important regulators of immunological processes and can be shuttled from cell to cell by MVs. The aim of our study was to analyze the the miRNA expression signature of MVs derived from γMSCs (γMSC-MVs), which may provide better understanding of the immunosuppressive property of their parent cells. Through miRNA microarray and bioinformatics analysis, we found 62 significantly differentially expressed miRNAs (DEMs) in γMSC-MVs compared with MSC-MVs. And the potential target genes and signaling pathways regulated by DEMs were predicted and analyzed. Interestingly, many DEMs and predicted signaling pathways had been demonstrated to be involved in immunoregulation. Furthermore, the network between immunoregulation-related pathways and relevant DEMs was constructed. Collectively, our research on the miRNA repertoires of γMSC-MVs not only provides new perspectives into the mechanisms underlying the enhanced immunosuppressive property of γMSCs, but also paves the way to clinical application of these potent organelles in the future.


Assuntos
Micropartículas Derivadas de Células/genética , Interferon gama/farmacologia , Células-Tronco Mesenquimais/imunologia , MicroRNAs/genética , Micropartículas Derivadas de Células/efeitos dos fármacos , Células Cultivadas , Biologia Computacional/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Análise de Sequência com Séries de Oligonucleotídeos , Transdução de Sinais
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