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BACKGROUND: There are no reliable molecular targets for early diagnosis and effective treatment in the clinical management of diabetic kidney disease (DKD). To identify novel gene factors underlying the progression of DKD. METHODS: The public transcriptomic datasets of the alloxan-induced DKD model and the streptozotocin-induced DKD model were retrieved to perform an integrative bioinformatic analysis of differentially expressed genes (DEGs) shared by two experimental animal models. The dominant biological processes and pathways associated with DEGs were identified through enrichment analysis. The expression changes of the key DEGs were validated in the classic db/db DKD mouse model. RESULTS: The downregulated and upregulated genes in DKD models were uncovered from GSE139317 and GSE131221 microarray datasets. Enrichment analysis revealed that metabolic process, extracellular exosomes, and hydrolase activity are shared biological processes and molecular activity is altered in the DEGs. Importantly, Hmgcs2, angptl4, and Slco1a1 displayed a consistent expression pattern across the two DKD models. In the classic db/db DKD mice, Hmgcs2 and angptl4 were also found to be upregulated while Slco1a1 was downregulated in comparison to the control animals. CONCLUSIONS: In summary, we identified the common biological processes and molecular activity being altered in two DKD experimental models, as well as the novel gene factors (Hmgcs2, Angptl4, and Slco1a1) which may be implicated in DKD. Future works are warranted to decipher the biological role of these genes in the pathogenesis of DKD.
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Diabetes Mellitus , Nefropatias Diabéticas , Camundongos , Animais , Nefropatias Diabéticas/metabolismo , Perfilação da Expressão Gênica , Biologia ComputacionalRESUMO
BACKGROUND: Previously, we could show that L-lactate affects cultured bovine granulosa cells (GC) in a specific manner driving the cells into an early pre-ovulatory phenotype. Here we studied genome wide effects in L-lactate-treated GC to further elucidate the underlying mechanisms that are responsible for the L-lactate induced transformation. Cultured estrogen producing GC treated either with L-lactate or vehicle control were subjected to mRNA microarray analysis. RESULTS: The analysis revealed 487 differentially expressed clusters, representing 461 annotated genes. Of these, 333 (= 318 genes) were identified as up- and 154 (= 143 genes) as down-regulated. As the top up-regulated genes we detected TXNIP, H19 and AHSG as well as our previously established marker transcripts RGS2 and PTX3. The top down-regulated genes included VNN1, SLC27A2 and GFRA1, but also MYC and the GC marker transcript CYP19A1. Pathway analysis with differentially expressed genes indicated "cAMP-mediated signaling" and "Axon guidance signaling" among the most affected pathways. Furthermore, estradiol, progesterone and Vegf were identified as potential upstream regulators. An effector network analysis by IPA provided first hints that processes of "angiogenesis" and "vascularization", but also "cell movement" appeared to be activated, whereas "organismal death" was predicted to be inhibited. CONCLUSIONS: Our data clearly show that L-lactate alters gene expression in cultured bovine GC in a broad, but obviously specific manner. Pathway analysis revealed that the mode of L-lactate action in GC initiates angiogenic processes, but also migratory events like cell movement and axonal guidance signaling, thus supporting the transformation of GC into an early luteal phenotype.
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Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Células da Granulosa/metabolismo , Lactatos/farmacologia , Transcriptoma , Animais , Bovinos , Feminino , Redes Reguladoras de Genes , Genoma , Células da Granulosa/citologia , Células da Granulosa/efeitos dos fármacosRESUMO
BACKGROUND/AIMS: Inflammatory processes are controlled by the fine-tuned balance of monocyte subsets. In mice, different subsets of monocytes can be distinguished by the expression of Ly6C that is highly expressed on inflammatory monocytes (Ly6Chigh) and to a lesser extent on patrolling monocytes (Ly6Clow). Our previous study revealed an accumulation of Ly6Chigh monocytes in atherosclerotic-prone mice bearing a deficiency in suppressor of cytokine signaling (SOCS)-1 leading to an increased atherosclerotic burden. To decipher the underlying mechanisms, we performed a genome-wide analysis of SOCS-1-dependent gene regulation in Ly6Chigh and Ly6Clow monocytes. METHODS: In monocyte subsets from SOCS-1competent and -deficient mice differentially regulated genes were identified using an Illumina mRNA microarray (45,200 transcripts), which were randomly validated by qPCR. Principal component analysis was performed to further characterize mRNA profiles in monocyte subsets. To unravel potential regulatory mechanisms behind the differential mRNA expression, in silico analysis of a transcription factor (TF) network correlating with SOCS-1-dependent mRNA expression was carried out and combined with a weighted correlation network analysis (WGCNA). RESULTS: mRNA analysis in monocyte subsets revealed 46 differentially regulated genes by 2-fold or more. Principal component analysis illustrated a distinct separation of mRNA profiles in monocyte subsets from SOCS-1-deficient mice. Notably, two cell surface receptors crucially involved in the determination of monocyte differentiation and survival, C-X3-C chemokine receptor 1 (CX3CR1) and colony stimulating factor 1 receptor (CSF1R), were identified to be regulated by SOCS-1. Moreover, in silico analysis of a TF network in combination with the WGCNA revealed genes coding for PPAR-γ, NUR77 and several ETSdomain proteins that act as pivotal inflammatory regulators. CONCLUSION: Our study reveals that SOCS-1 is implicated in a TF network regulating the expression of central transcription factors like PPAR-γ and NUR77 thereby influencing the expression of CX3CR1 and CSF1R that are known to be pivotal for the survival of Ly6Clow monocytes.
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Antígenos Ly , Aterosclerose/metabolismo , Regulação da Expressão Gênica , Monócitos/metabolismo , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/patologia , Sobrevivência Celular , Camundongos , Camundongos Knockout , Monócitos/patologia , Proteína 1 Supressora da Sinalização de Citocina/genéticaRESUMO
BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the leading cause of end-stage kidney disease. Previous mRNA microarray profiling studies of IgAN revealed inconsistent data. We sought to identify the aberrantly expressed genes and biological pathways by integrating IgAN gene expression datasets in blood cells and performing systematically experimental validation. We also explored the relationship between target genes and galactose-deficient IgA1 (Gd-IgA1) in IgAN. METHODS: We retrieved Gene Expression Omnibus (GEO) datasets of IgAN. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used for functional analysis. Deep sequencing on RNA isolated from B cells was used for microarray validation. The relationship between target mRNA expressions and Gd-IgA1 levels in serum were also studied. RESULTS: Three studies with microarray expression profiling datasets met our inclusion criteria. We identified 655 dyregulated genes, including 319 up-regulated and 336 down-regulated genes in three GEO datasets with a total of 35 patients of IgAN and 19 healthy controls. Based on biological process in GO term, these dyregulated genes are mainly related to pentose-phosphate shunt, non-oxidative branch, post-embryonic camera-type eye development and leukocyte activation. KEGG pathway analysis of microarray data revealed that these aberrantly expressed genes were enriched in human T-cell leukemia virus 1 infection, proteoglycans in cancer, intestinal immune network for IgA production and autophagy. We further performed deep sequencing on mRNAs isolated from B cells of an independent set of five patients with IgAN and three healthy persons with the same clinical and demographic characteristics. Seventy-seven genes overlapped with 655 differentially regulated genes mentioned above, including 43 up-regulated and thirty-four down-regulated genes. We next investigated whether these genes expression correlated with Gd-IgA1 levels in IgAN patients. Pearson correlation analyses showed PTEN (phosphatase and tensin homolog) was the most powerful gene negatively correlated with Gd-IgA1 levels. CONCLUSIONS: These results demonstrated that dyregulated genes in patients with IgAN were enriched in intestinal immune network for IgA production and autophagy process, and PTEN in B cells might be involved in the mechanism of Gd-IgA1 production.
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Galactose/sangue , Perfilação da Expressão Gênica , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/genética , Imunoglobulina A/sangue , RNA Mensageiro/genética , Adulto , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Masculino , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , RNA Mensageiro/metabolismo , Reprodutibilidade dos TestesRESUMO
BACKGROUND: The spatial relationship of glioblastoma (GBM) to the subventricular zone (SVZ) is associated with inferior patient survival. However, the underlying molecular phenotype is largely unknown. We interrogated an SVZ-dependent transcriptome and potential location-specific prognostic markers. METHODS: mRNA microarray data of a discovery set (n = 36 GBMs) were analyzed for SVZ-dependent gene expression and process networks using the MetaCore™ workflow. Differential gene expression was confirmed by qPCR in a validation set of 142 IDH1 wild-type GBMs that was also used for survival analysis. RESULTS: Microarray analysis revealed a transcriptome distinctive of SVZ+ GBM that was enriched for genes associated with Notch signaling. No overlap was found to The Cancer Genome Atlas's molecular subtypes. Independent validation of SVZ-dependent expression confirmed four genes with simultaneous prognostic impact: overexpression of HES4 (p = 0.034; HR 1.55) and DLL3 (p = 0.017; HR 1.61) predicted inferior, and overexpression of NTRK2 (p = 0.049; HR 0.66) and PIR (p = 0.025; HR 0.62) superior overall survival (OS). Additionally, overexpression of DLL3 was predictive of shorter progression-free survival (PFS) (p = 0.043; HR 1.64). Multivariate analysis revealed overexpression of HES4 to be independently associated with inferior OS (p = 0.033; HR 2.03), and overexpression of DLL3 with inferior PFS (p = 0.046; HR 1.65). CONCLUSIONS: We identified four genes with SVZ-dependent expression and prognostic significance, among those HES4 and DLL3 as part of Notch signaling, suggesting further evaluation of location-tailored targeted therapies.
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Neoplasias Encefálicas/genética , Glioblastoma/genética , Isocitrato Desidrogenase/genética , Receptores Notch/metabolismo , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Isocitrato Desidrogenase/metabolismo , Ventrículos Laterais/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Notch/genética , Transdução de Sinais , TranscriptomaRESUMO
Public microarray databases allow analysis of expression levels of candidate genes in different contexts. However, finding relevant microarray data is complicated by the large number of available studies. We have compiled a user-friendly, open-access database of mRNA microarray experiments relevant to allergic airway inflammation, the Allergic Airway Inflammation Repository (AAIR, http://aair.cimed.ike.liu.se/). The aim is to allow allergy researchers to determine the expression profile of their genes of interest in multiple clinical data sets and several experimental systems quickly and intuitively. AAIR also provides quick links to other relevant information such as experimental protocols, related literature and raw data files.
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Bases de Dados Genéticas , RNA Mensageiro , Hipersensibilidade Respiratória/genética , Transcriptoma , Humanos , NavegadorRESUMO
Osteosarcoma (OS) is a rare primary malignant bone tumor in adolescents and children with a poor prognosis. The identification of prognostic genes lags far behind advancements in treatment. In this study, we identified differential genes using mRNA microarray analysis of five paired OS tissues. Hub genes, gene set enrichment analysis, and pathway analysis were performed to gain insight into the pathway alterations of OS. Prognostic genes were screened using the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) dataset, then overlapped with the differential gene dataset. The carboxypeptidase E (CPE) gene, found to be an independent risk factor, was further validated using RT-PCR and Gene Expression Omnibus (GEO) datasets. Additionally, we explored the specific expression of CPE in OS tissues by reanalyzing single-cell genomics. Interestingly, CPE was found to be co-expressed with osteoblast lineage cell clusters that expressed RUNX2, SP7, SPP1, and IBSP marker genes in OS. These results suggest that CPE could serve as a prognostic factor in osteoblastic OS and should be further investigated as a potential therapeutic target.
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Neoplasias Ósseas , Osteossarcoma , Adolescente , Criança , Humanos , Carboxipeptidase H/genética , Prognóstico , Osteossarcoma/genética , Neoplasias Ósseas/genética , BiomarcadoresRESUMO
Hepatic sinusoidal obstruction syndrome (HSOS) is a serious side effect of oxaliplatin (OXA) treatment. The present study aimed to establish a reproducible mouse model of OXAinduced HSOS and to preliminarily explore the underlying molecular mechanisms using mRNA microarray analysis. A total of 45 C57BL/6 male mice were randomly divided into five groups: Control, 5 mg/kg OXA, 10 mg/kg OXA, 15 mg/kg OXA and 20 mg/kg OXA. The mice were respectively injected intraperitoneally with 5% glucose solution, or 5, 10, 15 or 20 mg/kg OXA solution once a week for 6 consecutive weeks. The body weight of the mice was recorded every day. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. Hematoxylin and eosin staining, Sirius red staining and scanning electron microscopy were used to identify pathological changes. mRNA microarray was used to analyze changes in the gene expression profiles mainly from the functional aspects of Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. The oxidation mechanism was verified by measuring oxidative stressrelated markers and reactive oxygen species with dihydroethidium probe technology, according to the microarray results. Among all of the OXA groups, 10 mg/kg OXA resulted in an acceptable survival rate of 78%. The mice showed obvious splenomegaly, increases in serum levels of ALT and AST, aggravation of liver pathological injuries and hepatic sinusoidal injuries. The microarray results suggested that mRNA expression changes after OXA treatment were associated with 'oxidative stress', 'coagulation function', 'steroid anabolism' and 'proinflammatory responses'. The results confirmed that OXA aggravated oxidative damage in the livers of the mice. The present study successfully established a mouse model of OXAinduced HSOS and preliminarily analyzed the underlying molecular mechanisms involved, thus laying a foundation for a subsequent indepth study.
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Hepatopatia Veno-Oclusiva , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Modelos Animais de Doenças , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Amarelo de Eosina-(YS)/uso terapêutico , Glucose/metabolismo , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Hematoxilina/uso terapêutico , Hepatopatia Veno-Oclusiva/induzido quimicamente , Hepatopatia Veno-Oclusiva/patologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries , Oxaliplatina/efeitos adversos , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Esteroides/metabolismoRESUMO
Background: In the present study, we used a computational method to identify Guillain-Barré syndrome (GBS) related genes based on (i) a gene expression profile, and (ii) the shortest path analysis in a protein-protein interaction (PPI) network. Materials and Methods: mRNA Microarray analyses were performed on the peripheral blood mononuclear cells (PBMCs) of four GBS patients and four age- and gender-matched healthy controls. Results: Totally 30 GBS-related genes were screened out, in which 20 were retrieved from PPI analysis of upregulated expressed genes and 23 were from downregulated expressed genes (13 overlap genes). Gene ontology (GO) enrichment and KEGG enrichment analysis were performed, respectively. Results showed that there were some overlap GO terms and KEGG pathway terms in both upregulated and downregulated analysis, including positive regulation of macromolecule metabolic process, intracellular signaling cascade, cell surface receptor linked signal transduction, intracellular non-membrane-bounded organelle, non-membrane-bounded organelle, plasma membrane, ErbB signaling pathway, focal adhesion, neurotrophin signaling pathway and Wnt signaling pathway, which indicated these terms may play a critical role during GBS process. Discussion: These results provided basic information about the genetic and molecular pathogenesis of GBS disease, which may improve the development of effective genetic strategies for GBS treatment in the future.
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Traumatic brain injury (TBI) is a complex injury with a multi-faceted recovery process. Long non-coding RNAs (lncRNAs) are demonstrated to be involved in central nervous system (CNS) disorders. However, the roles of lncRNAs in long-term neurological deficits post-TBI are poorly understood. The present study depicted the microarray's lncRNA and messenger RNA (mRNA) profiles at 14 days in TBI mice hippocampi. LncRNA and mRNA microarray was used to identify differentially expressed genes. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to validate the microarray results. Bioinformatics analysis [including Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, lncRNA-mRNA co-expression network, and lncRNA-miRNA-mRNA network] were applied to explore the underlying mechanism. A total of 264 differentially expressed lncRNAs and 232 expressed mRNAs were identified (fold change > 1.5 and P-value < 0.05). Altered genes were enriched in inflammation, immune response, blood-brain barrier, glutamatergic neurological effects, and neuroactive ligand-receptor, which may be associated with TBI-induced pathophysiologic changes in the long-term neurological deficits. The lncRNAs-mRNAs co-expression network was generated for 74 lncRNA-mRNA pairs, most of which are positive correlations. The lncRNA-miRNA-mRNA interaction network included 12 lncRNAs, 59 miRNAs, and 25 mRNAs. Numerous significantly altered lncRNAs and mRNAs in mice hippocampi were enriched in inflammation and immune response. Furthermore, these dysregulated lncRNAs and mRNAs may be promising therapeutic targets to overcome obstacles in long-term recovery following TBI.
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AIM: Several studies have demonstrated that increased omental adipose is a risk factor for obesity and metabolic syndrome. It remains unclear whether it is responsible for hypertension as an independent risk. This study was designed to assess the impact of omental adipose removal by surgery on blood pressure in cancer patients with or without hypertension. METHODS AND RESULTS: In this prospective observational study, 133 patients with gastric or gynecological cancer were divided into 3 groups: non-hypertensive and omentum removed (NH&OR), hypertensive and omentum removed (H&OR), and hypertensive and omentum present (H&OP). Patients were followed up with systolic and diastolic blood pressure (SBP and DBP), changes in related body mass index and metabolic indices. The time points of the 2 follow-up visits were 1 month ± 7 days after the operation before the start of chemotherapy and the endpoint of 8 ± 1 month. Omental adipose tissues from both non-hypertensive and hypertensive patients in surgery were collected. We included 133 patients (84.2% female, 20.3% malignant gastric cancer and 79.7% malignant gynecological cancer, 78.2% omentum removal, 48.9% hypertensive), and all completed follow-up. H&OR group showed significant reductions in systolic and diastolic blood pressure compared with the baseline at 1-m (-16.94/-10.50 mmHg, both P < 0.001) and 8-m end point (-16.00/-5.50 mmHg, P < 0.001 and P = 0.004). Little reductions were observed with the body mass index of patients in 3 groups till the endpoint of study (H&OR group: 24.60 kg/m2 to 23.57 kg/m2, NH&OR group: 23.45 kg/m2 to 23.25 kg/m2, H&OP group: 25.74 kg/m2 to 25.24 kg/m2, all P > 0.05). No correlation was found between the baseline body mass index and 8-m change of systolic and diastolic blood pressure in omentum removed groups. In both groups, triglyceride levels were significantly increased at 4 ± 1 week after surgery (NH&OR 0.32 mmol/L, P = 0.006; H&OR 0.40 mmol/L, P = 0.010). CONCLUSION: Resection of omental adipose tissue represents an effective strategy for reducing systolic and diastolic blood pressure at 8 months in hypertensive patients, even in the non-obese hypertensive population.
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Background: Aggressive juvenile-onset recurrent respiratory papillomatosis (JORRP) threatens patient lives if not receives immediate surgical intervene. Even with surgical intervene, complete remission of this disease is not approachable. Therefore, understanding the factors relevant to disease severity and prognosis will do help to the treatment strategy and health management of this disease.Objective: This study aimed to explore the clinic, laboratory and socioeconomic characteristics of patients and evaluate the risk factors for aggressive JORRP.Methods: The information of clinical and socioeconomic status of the patients was reviewed and its association with disease severity was analyzed. Papilloma from JORRP patients undergone surgeries was used to determine HPV subtypes by real-time PCR. The profiles of mRNA expression in the papilloma were assessed using microarray.Results: Age at diagnosis and socioeconomic status were shown to associate with the severity of JORRP. There was no differential severity considering different HPV subtype. The mRNA expression of nucleotide binding oligomerization domain receptor protein 3 (NLRP3) and Gasdermin B (GSDMB) was reduced in papillomas.Conclusions: A younger age at diagnosis and low socioeconomic status were associated with the severity of JORRP. mRNA expression of NLRP3 and GSDMB in the papillomas of JORRP patients was significantly reduced.Abbreviation: JORRP: Juvenile-onset recurrent respiratory papillomatosis; RRP: Recurrent respiratory papillomatosis; OSAS: Obstructive sleep apnea syndrome; NLRP3: Nucleotide binding oligomerization domain receptor protein 3; GSDMB: Gasdermin B.
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Idade de Início , Expressão Gênica , Infecções por Papillomavirus , RNA Neoplásico/metabolismo , Infecções Respiratórias , Classe Social , Povo Asiático , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Modelos Logísticos , Masculino , Infecções por Papillomavirus/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Recidiva , Infecções Respiratórias/genética , Fatores de RiscoRESUMO
BACKGROUND: Reverse phase protein array (RPPA) analysis, allows investigation of potential targets at the functional protein level,. We identified TNBC subtypes at the protein level using RPPA and compared them with mRNA molecular subtypes (TNBCtype, TNBCtype-4, and PAM50) that is unique in its availability of both RPPA and mRNA analyses. METHODS: We classified the samples from 80 TNBC patients using both k-means and hierarchical consensus clustering analysis and performed Ingenuity Pathway Analysis. We also investigated whether we could reproduce the mRNA molecular subtypes using the RPPA dataset. RESULTS: Both clustering methods divided all samples into 2 clusters that were biologically the same. The top canonical pathways included inflammation, hormonal receptors, and MAPK signaling pathways for the first cluster ["inflammation and hormonal-related (I/H) subtype"] and the GADD45, DNA damage, and p53 signaling pathways for the second cluster ["DNA damage (DD)-related subtype"]. Further k-means cluster analysis identified 5 TNBC clusters. Comparison between sample classification using the 5 RPPA-based k-means cluster subtypes and 6 gene-expression-based TNBCtype molecular subtypes showed significant association between the 2 classifications (p = 0.017). CONCLUSIONS: The I/H and DD subtypes identified by RPPA advance our understanding of TNBC's heterogeneity from the functional proteomic perspective.
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Non-small cell lung cancers harboring somatic gain-of-function mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain respond well to treatment with EGFR tyrosine kinase inhibitors (TKIs) including gefitinib and erlotinib. However, all patients who experience a marked improvement with these drugs eventually develop disease progression due to the acquisition of drug resistance. Approximately half of the cases with acquired resistance to EGFR TKIs can be accounted for by a second-site mutation in exon 20 of the EGFR kinase domain (T790M). However, the changes of gene expression involved in EGFR TKI resistance due to the T790M mutation remain poorly defined. The present study established lung cancer cell lines that were resistant to gefitinib or erlotinib, and these cell lines were verified to contain the EGFR T790M mutation. The differential expression of genes associated with acquired resistance was verified in the present study by mRNA microarray analysis. Among the genes whose expression was significantly altered, genes whose expression was altered in gefitinib- and erlotinib-resistant cells were focused on. Notably, a total of 1,617 genes were identified as being differentially expressed in gefitinib- and erlotinib-resistant cells. Indeed, Gene ontology analysis revealed altered expression of genes involved in the regulation of cellular proliferation, apoptosis, and the cell cycle in EGFR TKI-resistant cells. The present results demonstrate distinctive gene expression patterns of EGFR TKI-resistant lung cancer cells with the EGFR T790M mutation. The present study can provide key insights into gene expression profiles involved in conferring resistance to EGFR TKI therapy in lung cancer cells.
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Identifying effective targets induced by ECM stiffness is of critical importance for treating metastatic cancer diseases, which are followed by changes in the mechanical microenvironment in cancer cells. In this study, polyacrylamide hydrogel substrates with different stiffnesses were prepared and mRNA microarrays were performed to analyze the mRNA expression profiles in breast cancer cell line SK-BR-3 grown on different stiffness substrates. The results indicated that the expressions of 1831 genes were changed significantly in the SK-BR-3 cells on the different stiffness substrates. GO and KEGG pathway analyses of the differently expressed genes in five significant profiles annotated that the most significant pathways were cell cycle, ubiquitin mediated proteolysis RNA transport and pathways in cancer. Finally, the network of genes and gene interaction based on these differently expressed genes was established, and the phosphorylation of AKT and ERK, respectively the downstreams of the PI3K and Ras signal pathways, was further validated. The genes identified in this study may represent good therapeutic targets, and further study of these targets may help to increase our understanding of the mechanisms underlying the pathological processes and therapy for metastatic breast cancer disease.
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Neoplasias da Mama/genética , RNA Mensageiro/metabolismo , Neoplasias da Mama/patologia , Biologia Computacional , Feminino , Humanos , Análise Serial de Tecidos , Microambiente TumoralRESUMO
Integrative analysis of microRNA (miRNA) and messenger RNA (mRNA) in Chronic Myeloid leukemia (CML) stem cells is an important technique to study the involvement of miRNA and their targets in CML stem cells self-renewal, maintenance, and therapeutic resistance. Here, we describe a simplified integrative analysis using Ingenuity Pathway Analysis software after performing proper RNA extraction, miRNA and mRNA microarray and data analysis.
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Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , MicroRNAs/genética , RNA Mensageiro/genética , Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Análise de Sequência de RNA , SoftwareRESUMO
Variation in the differentiation capacity of induced pluripotent stem cells (iPSCs) to specific lineages is a significant concern for their use in clinical applications and disease modeling. To identify factors that affect differentiation capacity, we performed integration analyses between hematopoietic differentiation performance and molecular signatures such as gene expression, DNA methylation, and chromatin status, using 35 human iPSC lines and four ESC lines. Our analyses revealed that hematopoietic commitment of PSCs to hematopoietic precursors correlates with IGF2 expression level, which in turn depends on signaling-dependent chromatin accessibility at mesendodermal genes. Maturation capacity for conversion of PSC-derived hematopoietic precursors to mature blood associates with the amount and pattern of DNA methylation acquired during reprogramming. Our study therefore provides insight into the molecular features that determine the differential capacities seen among human iPSC lines and, through the predictive potential of this information, highlights a way to select optimal iPSCs for clinical applications.
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Diferenciação Celular/genética , Epigênese Genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Ativinas/metabolismo , Animais , Sequência de Bases , Linhagem Celular , Linhagem da Célula/genética , Reprogramação Celular/genética , Cromatina/química , Metilação de DNA/genética , Células Eritroides/citologia , Células Eritroides/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Redes Reguladoras de Genes , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Fator de Crescimento Insulin-Like II/metabolismo , Megacariócitos/citologia , Megacariócitos/metabolismo , Camundongos SCID , Transdução de Sinais/genética , Transplante de Células-Tronco , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismoRESUMO
The C/EBP homologous protein CHOP is normally present at low levels in cells but increases rapidly after insults such as DNA damage or endoplasmatic reticulum stress where it contributes to cellular homeostasis and apoptosis. By forming heterodimers with other transcription factors, CHOP can either act as a dominant-negative regulator of gene expression or to induce the expression of target genes. Recent work demonstrated that seizure-induced hippocampal damage is significantly worse in mice lacking CHOP and these animals go on to develop an aggravated epileptic phenotype. To identify novel CHOP-controlled target genes which potentially influence the epileptic phenotype, we performed a bioinformatics analysis of tissue microarrays from chop-deficient mice after prolonged seizures. GO analysis revealed genes associated with biological membranes were prominent among those in the chop-deficient array dataset and we identified myelin-associated genes to be particularly de-repressed. These data suggest CHOP might act as an inhibitor of myelin-associated processes in the brain and could be targeted to influence axonal regeneration or reorganisation.
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Analysis of cellular pathways and networks in terms of logic relations is important to decipher the networks of molecular interactions that underlie cellular function.A computational approach for identifying lower and higher order gene logic associations was presented on the base of graph coloring theory and applied it to the colon cancer mRNA microarray data.Then the logic relationships of 51 oncogenes and cancer suppressor genes are analyzed and the logic association network of them was constructed.The signal pathway of TGF? from the network model was found and verified by the colon cancer pathway of KEGG.The model reveals many higher order logic relationships of cancer genes.These relationships illustrate the complexities that arise in cancer cellular networks because of interacting pathways.The results show that this method is feasible and is expected to give a reference to the medical molecular biologist.