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Results for “expression profiling”

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PubMed2004

Gene expression profiling in Barrett's esophagus and cardia intestinal metaplasia: a comparative analysis using cDNA microarray.

AIM: To study the difference of gene expression profile changes in Barrett's esophagus (BE) and cardia intestinal metaplasia (CIM) and to screen the novel genes in the early stage by cDNA microarray. METHODS: cDNA retrotranscribed from an equal amount of mRNA from BE and CIM epithelial tissues was labeled with Cy3 and Cy5 fluorescence as probes. The mixed probe was hybridized with three pieces of BiostarH-40 s double dot human whole gene chip. The chips were scanned with a ScanArray 4000. The acquired images were analyzed using GenePix Pro 3.0 software. RESULTS: A total of 141 genes were screened out that exhibited different expression in all three chips. There were 74 upregulated and 67 downregulated genes in gene expression profiles of BE which were two times of that in CIM. CONCLUSION: There is a difference in gene expression level between BE and CIM epithelia. These 141 genes probably relate to the occurrence and development of BE and the progression to adenocarcinoma.

Adenocarcinoma↗

PubMed2000

Differential pituitary gene expression profiles associated- to aging and spontaneous tumors as revealed by rat cDNA expression array.

Aging of the rat pituitary is often accompanied by the occurrence of adenomas. We asked whether complementary DNA hybridization array was adapted to identify gene expression patterns linked to aging and associated spontaneous adenomas. Thus, [32P]dATP-labeled cDNAs were prepared from pituitaries of three month-old rats (Y) and tumor-bearing 20-28-month-old rats (OT). The cDNAs were hybridized to identical membrane arrays allowing to study simultaneously 588 known genes (Clontech 7738-1). Among the 79 genes detected, the GH gene was predominantly expressed in both groups. Twenty-eight genes in the OT group and 15 in the Y group were found to be expressed at a higher level. The largest differences were of about 17 fold and were observed for the galanin and glutathione S transferase genes in the Y and OT groups, respectively. Relative RT-PCR was applied to validate the OT versus Y expression pattern obtained via cDNA array hybridization. The results were consistent for 14 out the 15 genes tested. In the light of these results, differential membrane array hybridization appears suitable to identify gene expression profiles associated with pituitary aging.

Adenoma↗

PubMed2004

Cytokeratin expression profile in gastric carcinomas.

Cytokeratin (CK) is observed mainly in epithelial cells, and the diverse expression pattern of CK subtypes may be helpful in discriminating between primary and metastatic carcinomas in various organs, including the stomach. To clarify the CK expression profiles in gastric carcinomas, 329 consecutive specimens were immunohistochemically evaluated in terms of their CK subtypes using the tissue array method. The overall positive rates were 84.7% for CK4, 3.2% for CK5, 28.7% for CK6, 71.1% for CK7, 96.6% for CK8, 0% for CK10, 81.6% for CK13, 0.3% for CK14, 4.1% for CK16, 0% for CK17, 99.4% for CK18, 89.7% for CK19, and 30.0% for CK20. Well-differentiated or moderately differentiated carcinomas were related to several CKs, and mucinous carcinoma was associated with CK20 expression. Interestingly, CK7 and CK20 expression was associated with the mucin phenotype of gastric carcinoma, but this association had no diagnostic value. Epstein-Barr virus (EBV)-associated gastric carcinomas showed a tendency toward negative expression of CK7. CK6 expression was related to microsatellite instability (MSI), early pTNM stage, and better clinical outcome. In conclusion, CK expression profiles in consecutive gastric carcinomas demonstrate heterogeneity, and no single CK has diagnostic value by itself. CK expression is associated with various clinicopathologic parameters, mucin phenotype, EBV positivity, MSI status, and patient survival.

Biomarkers, Tumor↗

PubMed2006

Bruch membrane aging alters the gene expression profile of human retinal pigment epithelium.

We investigated the effects of age-related changes within the Bruch membrane on the gene expression profile of the RPE. Immortalized human ARPE-19 cells were seeded onto acellular human Bruch membrane from younger and older donors and harvested 72 hr later; total RNA was isolated and the gene expression profile was determined using the Affymetrix Human Genome U95A gene chip. Twelve genes were upregulated and 8 genes were downregulated with Bruch membrane aging; RT-PCR confirms that Bruch membrane aging upregulates genes in RPE cells encoding for transforming growth factor alpha and downregulates genes for vitronectin and the membrane transporter ABCC5. The role of these changes in the pathogenesis of age-related diseases such as macular degeneration remains to be elucidated.

Adult↗

PubMed2005

Prediction of lymph node metastasis by analysis of gene expression profiles in primary lung adenocarcinomas.

PURPOSE: Lymph node status is a strong predictor of outcome for lung cancer patients. Recently, several reports have hinted that gene expression profiles of primary tumor may be able to predict node status. The goals of this study were to determine if microarray data could be used to accurately classify patients with regard to pathologic lymph node status, and to determine if this analysis could identify patients at risk for occult disease and worse survival. EXPERIMENTAL DESIGN: Two previously published lung adenocarcinoma microarray data sets were reanalyzed. Patients were separated into two groups based on pathologic lymph node positive (pN+) or negative (pN0) status, and prediction analysis of microarray (PAM) was used for training and validation to classify nodal status. Overall survival analysis was performed based on PAM classifications. RESULTS: In the training phase, a 318-gene set gave classification accuracy of 88.4% when compared with pathology. Survival was significantly worse in PAM-positive compared with PAM-negative patients overall (P < 0.0001) and also when confined to pN0 patients only (P = 0.0037). In the validation set, classification accuracy was again 94.1% in the pN+ patients but only 21.2% in the pN0 patients. However, among the pN0 patients, recurrence rates and overall survival were significantly worse in the PAM-positive compared with PAM-negative patients (P = 0.0258 and 0.0507). CONCLUSIONS: Analysis of gene expression profiles from primary tumor may predict lymph node status but frequently misclassifies pN0 patients as node positive. Recurrence rates and overall survival are worse in these "misclassified" patients, implying that they may in fact have occult disease spread.

Adenocarcinoma↗

PubMed2006

Dissecting Oct3/4-regulated gene networks in embryonic stem cells by expression profiling.

POU transcription factor Pou5f1 (Oct3/4) is required to maintain ES cells in an undifferentiated state. Here we show that global expression profiling of Oct3/4-manipulated ES cells delineates the downstream target genes of Oct3/4. Combined with data from genome-wide chromatin-immunoprecipitation (ChIP) assays, this analysis identifies not only primary downstream targets of Oct3/4, but also secondary or tertiary targets. Furthermore, the analysis also reveals that downstream target genes are regulated either positively or negatively by Oct3/4. Identification of a group of genes that show both activation and repression depending on Oct3/4 expression levels provides a possible mechanism for the requirement of appropriate Oct3/4 expression to maintain undifferentiated ES cells. As a proof-of-principle study, one of the downstream genes, Tcl1, has been analyzed in detail. We show that Oct3/4 binds to the promoter region of Tcl1 and activates its transcription. We also show that Tcl1 is involved in the regulation of proliferation, but not differentiation, in ES cells. These findings suggest that the global expression profiling of gene-manipulated ES cells can help to delineate the structure and dynamics of gene regulatory networks.

Animals↗

PubMed2004

Genome-wide expression profiling of RNA interference of hepatitis B virus gene expression and replication.

Small interfering RNA (siRNA) has been used repeatedly to down-regulate viral gene expression and inhibit viral replication in mammalian cells. In this study, we showed that siRNAs specific for two conserved regions within the hepatitis B S antigen (HBsAg) gene can inhibit antigen production in two human liver cell lines which constitutively produce and secrete HBsAg. The inhibitory effect was concentration dependent for both PLC/PRF/5 and 2.2.15 cells. Decreases in the corresponding viral transcript levels were observed. The inhibitory effect was observed within 24 h and was still evident 7 days after the initial treatment with siRNA. A significant reduction in virion production was also observed for the 2.2.15 cells. A critical consideration in this study was the specificity of the siRNA-mediated inhibition. To address this, we first examined the effects on cell growth and viability. These were not affected in either cell line. cDNA microarrays were also used to examine genome-wide changes in gene regulation. No significant off-target gene regulation was observed in either cell line. Our findings thus indicate that siRNA can specifically mediate the down-regulation of viral gene expression leading to a reduction in virion production.

Gene Expression Profiling↗

PubMed2006

Global protein expression profiling underlines reciprocal regulation of caveolin 1 and endothelial nitric oxide synthase expression in ovariectomized sheep uterine artery by estrogen/progesterone replacement therapy.

Ovariectomized (OVX) ewes were assigned to receive vehicle, progesterone (P4, 0.9-g controlled internal drug release vaginal implants), estradiol-17beta (E2, 5 microg/kg bolus + 6 microg kg(-1) day(-1)), or P4 + E2 for 10 days (n = 3/group). Uterine artery endothelial proteins were mechanically isolated on Day 10. The samples were used for protein expression profiling by the Ciphergen Proteinchip system and immunoblotting analysis of endothelial nitric oxide synthase (NOS3, also termed eNOS) and caveolin 1. Uterine artery rings were cut and analyzed by immunohistochemistry to localize NOS3 and caveolin 1 expression. With the use of the IMAC3 protein chip with loading as little as 2 microg protein/sample, many protein peaks could be detected. Compared to vehicle controls, a approximately 133.1-kDa protein was identified to be upregulated by 2- to 4-fold in OVX ewes receiving E2, P4, and their combination, whereas a approximately 22.6-kDa protein was downregulated by 2- to 4-fold in OVX ewes receiving E2 and E2/P4, but not P4 treatments. Western blot analysis revealed that E2, P4, and their combination all increased NOS3 protein, whereas E2 and its combination with P4, but not P4 alone, downregulated caveolin 1 expression. Immunohistochemical analysis revealed that NOS3 was mainly localized in the endothelium and upregulated by E2, whereas caveolin 1 was localized in both endothelium and smooth muscle and downregulated by E2. Thus, our data demonstrate that uterine artery endothelial NOS3 and caveolin 1 are regulated reciprocally by estrogen replacement therapy. In keeping with the facts that E2, but not P4, causes uterine vasodilatation and that E2 and P4 increase NOS3 expression, but only E2 decrease caveolin 1 expression, our current study suggests that both increased NOS3 expression and decreased caveolin 1 expression are needed to facilitate estrogen-induced uterine vasodilatation.

Animals↗

PubMed2002

Gene expression profiles in human cardiac cells subjected to hypoxia or expressing a hybrid form of HIF-1 alpha.

The cellular response to hypoxia depends on rapid posttranslational modifications of proteins as well as regulation of gene expression. We performed serial analysis of gene expression (SAGE) on human cardiac cells under normoxia, subjected to hypoxia, or infected with Ad2/HIF-1alpha/VP16 (an adenoviral vector expressing a stable hybrid form of hypoxia-inducible factor 1alpha) or Ad2/CMVEV (an empty vector). Of the 97,646 SAGE tags that were sequenced, 27% matched GenBank entries, while an additional 32% matched expressed sequence tags (ESTs) in UniGene. We analyzed 161 characterized genes or ESTs with a putative identification. Expression of 35, 11, and 46 genes was increased by hypoxia, infection with Ad2/EVCMV, or infection with Ad2/HIF-1alpha/VP16, respectively, compared with normoxia; conversely, 20, 11, 38 genes, respectively, were expressed at lower levels. Genes regulated by hypoxia were associated with transcription, biosynthesis, extracellular matrix formation, glycolysis, energy production, cell survival, and cell stress. Changes following infection with Ad2/HIF-1alpha/VP16 mimicked the hypoxic response to a certain extent. Infection with Ad2/CMVEV affected expression of genes that were associated with extracellular matrix formation and membrane trafficking. Differential expression of select genes was confirmed using TaqMan in additional human cardiac cells and rat neonatal ventricular myocytes. These data provide insight into gene expression underlying the diverse and complex cellular response to hypoxia, expression of HIF-1alpha/VP16, or adenoviral infection.

Adenoviridae↗

PubMed2005

Gene expression profiling of rat midbrain dopamine neurons: implications for selective vulnerability in parkinsonism.

To elucidate factors related to selective dopamine neuron degeneration in Parkinson's disease (PD), we have defined gene expression profiles of discrete dopamine neuron subpopulations in the rat using immunofluorescent laser capture microscopy and microarray analysis. Although profiles were remarkably similar, there are concerted categorical differences in gene expression between dopamine neurons that might explain their differential susceptibility. As a group, energy metabolism transcripts are more highly expressed in substantia nigra (SN) dopamine neurons, an intriguing result considering previous evidence for a mitochondrial defect in idiopathic PD and the greater susceptibility of SN dopamine neurons to damage by mitochondrial poisons. Examination of putative transcription factor binding sites suggests that these concerted differences may be related to differential activity of specific transcription factors. These results provide the first large scale description of gene expression profiles of dopamine neurons and suggest several avenues for investigation into dopaminergic neuroprotective therapy for PD.

Animals↗

PubMed2004

Intracellular expression profiling by laser capture microdissection: three novel components of the neuromuscular junction.

The neuromuscular junction (NMJ) is a regionally specialized area of myofibers defined, in part, by specific gene expression from underlying myonuclei. We sought to obtain a more complete picture of the mRNA transcripts and proteins playing a role in NMJ formation and maintenance using laser capture microdissection (LCM) and to define expression profiles of the nuclear domain at the NMJ. NMJs (800) were isolated from normal mouse tibialis anterior muscle by LCM, with an equal amount of adjacent non-NMJ regions isolated. Many known components of the NMJ were found significantly differentially expressed. Three differentially expressed potential novel components of the NMJ were chosen for further study, and each was validated by immunostaining with and without blocking peptides (3/3), quantitative RT-PCR (3/3), and in situ hybridization (1/3). The three genes validated were dual-specificity phosphatase-6 (DUSP6), ribosomal receptor-binding protein-1 (RRBP1), and vacuolar protein sorting-26 (VPS26). Query of each of these novel components in a 27-time point in vivo muscle regeneration series showed expression commensurate with previously known NMJ markers (nestin, alpha-ACh receptor). Understanding and discovering elements responsible for the integrity and function of NMJs is relevant to understanding neuromuscular diseases such as spinal muscular atrophy. Our LCM-based mRNA expression profiling provided us with new means of identification of specific genes potentially responsible for NMJ stability and function and new candidates for involvement in disease pathogenesis.

Acetylcholinesterase↗

PubMed2003

The gene expression response of breast cancer to growth regulators: patterns and correlation with tumor expression profiles.

The effects of hormone and growth factor signaling on gene expression contribute significantly to breast tumorigenesis and disease progression; however, the targets of signaling networks associated with deregulated growth are not well understood. We defined the dynamic transcriptional effects elicited in MCF7, T-47D, and MDA-MB-436 breast cancer cell lines by nine regulators of growth and differentiation (17beta-estradiol, antiestrogens fulvestrant and tamoxifen, progestin R5020, antiprogestin RU486, all-trans-retinoic acid, epidermal growth factor, mitogen-activated protein/extracellular signal-regulated kinase 1/2 inhibitor U0126 and phorbol ester 12-O-tetradecanoylphorbol-13-acetate) and compared the patterns of gene regulation to published tumor expression profiles. The complex pattern of response to these agents revealed unexpected relationships between their effects, including a profound overlap in genes regulated by both steroids and epidermal growth factor, and striking overlaps between fulvestrant and all-trans-retinoic acid. Estrogen-responsive genes could be divided into two major clusters, only one of which is associated with cell proliferation. Gene ontology analysis was used to highlight functionally distinct biological responses to different mitogens. Significant correlations were identified between several clusters of drug-responsive genes and genes that discriminate estrogen receptor status or disease outcome in patient samples. The majority of estrogen receptor status discriminators were not responsive in our dataset and are therefore likely to reflect underlying differences in histogenesis and disease progression rather than growth factor signaling. This article highlights the overall impact at the gene expression level of diverse regulators of breast cancer growth and links the behavior of breast cancer cells in culture to important clinical properties of human breast tumors.

Algorithms↗

PubMed2002

Identification of gene expression profiles that segregate patients with childhood leukemia.

To identify genes whose expression correlated with biological features of childhood leukemia, we prospectively analyzed the expression profiles of 4608 genes using cDNA microarrays in 51 freshly processed bone marrow samples from children with acute leukemia, over a 24-month period, at a single institution. Two supervised methods of analysis were used to identify the 20 best discriminating genes between the following cohorts: acute myelogenous leukemia (AML) versus acute lymphoblastic leukemia (ALL); B-lineage versus T-lineage ALL; newly diagnosed B-lineage standard-risk versus high-risk ALL; and B-lineage leukemia harboring the TEL-AML 1 fusion versus patients without a molecularly characterized translocation. These methods identified overlapping sets of genes that segregated patients within described subgroups. Cross-validation demonstrated that the majority of patients could be correctly classified based on these genes alone, and hierarchical clustering grouped patients with similar clinical and biological disease features. The potential for select genes to discriminate patients was validated using real-time PCR in samples that were analyzed by microarray profiling and in other uniformly processed leukemic marrow samples. As expected, microarray technology can successfully segregate patients defined by traditional measures such as immunophenotype and cytogenetic alterations. However, among specific subgroups, this preliminary analysis also suggests that microarrays can identify unanticipated similarities and diversity in individual patients and thus may be useful in augmenting risk-group stratification in the future.

Child↗

PubMed2002

[Exploitation of expression profiles: examples in oncology].

The analysis of biological processes has been revolutionized by the emergence of the DNA array technology. As cellular biological events are controlled by gene expression, their modulations are markers of the cellular activity. These modulations can be indicative of either a physiological process or a pathological one. Monitoring of the expression levels of thousands of genes simultaneously, the expression profiling method is based upon comparative studies where the identification of the differentially expressed genes in two samples is aimed. The two samples under study may be compared temporally or following drug treatment, they may also originate from different sources, e.g. normal versus pathological samples. In that case, gene expression profiling is conducted for diagnostics purposes or therapy monitoring, and offers an opportunity to identify new drug targets. Using different examples, we describe the potentialities of this approach in oncology.

Antineoplastic Agents↗

PubMed2001

Expression profiling suggested a regulatory role of liver-enriched transcription factors in human hepatocellular carcinoma.

By using a cDNA array representing 14,000 cDNA clusters, we studied the expression profiles in paired clinical hepatocellular carcinoma (HCC) samples and the distal nontumorous liver tissues from the same patients. Despite the significant heterogeneity among the clinical samples, 72 genes (including 30 novel genes) were down-regulated and 84 genes (including 48 novel genes) were up-regulated in >50% of the cancer samples that were identified. The alterations in gene expression levels were confirmed by Northern blot and reverse-transcription PCR in all of 4 randomly selected genes. It was conspicuous that 21 of 38 hepatocarcinoma (HCC) down-regulated genes studied previously were reportedly regulated by a group of liver-enriched transcription factors (LETFs), and 12 of 36 HCC up-regulated genes studied previously were involved in protein translation. Reexamination of the cDNA array data further revealed that most of the genes known to be regulated by LETFs were down-regulated in at least a portion of the HCC samples. Among the LETFs, the expression level of CCAAT/enhancer-binding protein (C/EBP) alpha was down-regulated in cancer, whereas hepatocyte nuclear factor 1 (HNF-1), HNF-3beta, HNF-4alpha, and HNF-4gamma were up-regulated. The expression profiling thus suggested multiple regulatory pathways involved in HCC, especially that related to LETFs.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗

PubMed2006

Gene expression profile in immunologically injured liver cell of mice.

To study the gene expression profiles between immunologically injured liver cell and normal liver cell of mice and to screen on a large scale the differentially expressed genes associated with the formation of liver injury, the experimental mice were randomly divided into the normal group for controlling and the immunologically liver-injured group induced by BCG and LPS. The liver mRNA of the two groups were extracted respectively and reversely-transcribed to cDNA with the incorporation of different fluorescence (Cy3, Cy5) labeled dUTP as the hybridization probes. The mixed probes were hybridized to the cDNA microarray chips. The fluorescent signal results were acquired by scanner ScanArray 4000 and analyzed with software GenePix Pro 3.0. Among the 14112 target genes, 293 genes were found to be significantly differentially expressed, in which 188 genes were up-regulated and 105 genes were down-regulated. Based on the analysis of biological functions of those differentially expressed genes, it was indicated that the occurrence and development of mouse liver damage induced by BCG and LPS were highly correlated with the processes of immune reactions, cell synthesis, metabolism, apoptosis and transportation in liver cell, which might be quite important for elucidating the regulatory network of gene expression associated with the liver damage, also important for finally discovering the pathogenic mechanisms of immunological liver damage.

Alanine Transaminase↗

PubMed2002

Chromosome 1q expression profiling and relapse in Wilms' tumour.

Gene-expression patterns have proved useful for tumour classification and prediction of prognosis. We investigated a new gene-expression profiling method that targets individual chromosomes--comparative expressed sequence hybridisation (CESH)--to establish if any expression pattern was associated with relapse, and if this pattern could accurately predict outcome. We studied 18 cases of Wilms' tumour with favourable histological findings. Relative overexpression of genes on the long arm of chromosome 1 was shown in all tumours that subsequently relapsed but in none of those from patients in remission (odds ratio 357, 95% CI 6.4-19960). This finding shows the value of CESH analysis to rapidly screen for chromosomal regions that carry genes whose differential expression is important in establishment of tumour behaviour.

Child↗

PubMed2004

Detection of cancer-related gene expression profiles in severe cervical neoplasia.

The molecular signatures of 20 severe cervical intraepithelial neoplasia (CIN3) cases and 10 cervical squamous cell cancers were determined to define cancer-related gene expression profiles. RNAs extracted from microdissected tissues were amplified by SMART technology and used as probes for hybridization of commercially available cDNA array filters comprising 1,176 cancer-related genes. Ninety-two differentially expressed genes were identified by comparison of pooled cDNA from CIN3 vs. cervical cancer. Heterogeneity in expression of this subset of genes was then analyzed for each biopsy using an algorithm for self-organizing maps. For several gene clusters, the expression pattern for CIN3 differed significantly from that of cancer. Moreover, hierarchical clustering revealed significant differences in distribution of CIN and cancer. Several CIN cases were more strongly related to cancer, suggesting that gene expression profiling may be useful for subdividing pathologically indistinguishable precancers into different biologic entities. This approach also provides a basis for the identification of putative prognostic markers and for targeted molecular therapy.

Adult↗