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PubMed2005

Gene expression profiles in human gastric cancer: expression of maspin correlates with lymph node metastasis.

To seek for a candidate gene that would regulate tumour progression and metastasis in gastric cancer, we investigated gene expression profiles by using DNA microarray. Tumour tissue and adjacent normal tissue were obtained from 21 patients with gastric cancer and then examined for their gene expression profiles by the Gene Chip Human U95Av2 array, which includes 12 000 human genes and EST sequences. A total of 25 genes were upregulated and two genes were downregulated by at least four-fold in the tumour tissue. In a further analysis according to lymph node metastasis, the expressed levels of maspin, as well as carcinoembryonic antigen and nonspecific crossreacting antigen were significantly higher in tumours with lymph node metastasis than in those without it. Maspin expression in 85 gastric cancer patients was further investigated by using immunohistochemistry. Maspin expression was not observed in normal gastric epithelia without intestinal metaplasia. In contrast, maspin was expressed in 74 of 85 tumour tissues. There was a significant correlation between the incidence of maspin-positive tumour staining and lymph node metastasis. These results suggest that maspin has a potential role for tumour metastasis in gastric cancer.

Adult↗

PubMed2000

Gene expression profile and identification of differentially expressed transcripts during human intrathymic T-cell development by cDNA sequencing analysis.

The development of immature thymocytes to mature T-lymphocytes is a central process for establishing a functional immune system. The gene regulatory events involved in this process are of outstanding interest in understanding the generation of the T-cell repertoire as well as the differentiation of lineage-specific cells, such as CD4(+) helper T-cells or CD8(+) cytotoxic T-lymphocytes. While some essential genes involved in lineage decision and thymocyte differentiation have been already identified, the exact regulatory mechanisms and differential gene expressions are still unknown. The present study was performed to analyze the gene expression profile during T-cell development, in particular, during the differentiation of immature thymocytes into CD4(+) mature T-cells by analyses of expressed sequence tags (ESTs), and to elucidate novel human genes involved in this process. Based on distinct developmental stages, three PCR-based cDNA libraries from immature CD3(-),4(-),8(-) triple-negative, CD4(+),8(+) double-positive, and mature CD4(+),8(-) single-positive thymocytes were constructed. A total of 1477 randomly selected clones were analyzed by automated single-pass sequencing, and the assembly of ESTs resulted in 1027 different species of contig sequences. Among them, 392 contig sequences were matched to known genes, and several novel transcripts were discovered. The matched clones were classified into seven categories according to their functional aspects, and the gene expression profiles of the three thymocyte subsets were compared. The information obtained in current study will serve as a valuable resource for elucidating the molecular mechanism of intrathymic T-cell development.

Cell Differentiation↗

PubMed2006

Expression profiling identifies altered expression of genes that contribute to the inhibition of transforming growth factor-beta signaling in ovarian cancer.

Ovarian cancer is resistant to the antiproliferative effects of transforming growth factor-beta (TGF-beta); however, the mechanism of this resistance remains unclear. We used oligonucleotide arrays to profile 37 undissected, 68 microdissected advanced-stage, and 14 microdissected early-stage papillary serous cancers to identify signaling pathways involved in ovarian cancer. A total of seven genes involved in TGF-beta signaling were identified that had altered expression >1.5-fold (P < 0.001) in the ovarian cancer specimens compared with normal ovarian surface epithelium. The expression of these genes was coordinately altered: genes that inhibit TGF-beta signaling (DACH1, BMP7, and EVI1) were up-regulated in advanced-stage ovarian cancers and, conversely, genes that enhance TGF-beta signaling (PCAF, TFE3, TGFBRII, and SMAD4) were down-regulated compared with the normal samples. The microarray data for DACH1 and EVI1 were validated using quantitative real-time PCR on 22 microdissected ovarian cancer specimens. The EVI1 gene locus was amplified in 43% of the tumors, and there was a significant correlation (P = 0.029) between gene copy number and EVI1 gene expression. No amplification at the DACH1 locus was found in any of the samples. DACH1 and EVI1 inhibited TGF-beta signaling in immortalized normal ovarian epithelial cells, and a dominant-negative DACH1, DACH1-Delta DS, partially restored signaling in an ovarian cancer cell line resistant to TGF-beta. These results suggest that altered expression of these genes is responsible for disrupted TGF-beta signaling in ovarian cancer and they may be useful as new and novel therapeutic targets for ovarian cancer.

Female↗

PubMed2003

Molecular pharmacology of cancer therapy in human colorectal cancer by gene expression profiling.

Global gene expression profiling has potential for elucidating the complex cellular effects and mechanisms of action of novel targeted anticancer agents or existing chemotherapeutics for which the precise molecular mechanism of action may be unclear. In this study, decreased expression of genes required for RNA and protein synthesis, and for metabolism were detected in rectal cancer biopsies taken from patients during a 5-fluorouracil infusion. Our observations demonstrate that this approach is feasible and can detect responses that may have otherwise been missed by conventional methods. The results suggested new mechanism-based combination treatments for colorectal cancer and demonstrated that expression profiling could provide valuable information on the molecular pharmacology of established and novel drugs.

Adult↗

PubMed2006

Biologically relevant effects of mRNA amplification on gene expression profiles.

BACKGROUND: Gene expression microarray technology permits the analysis of global gene expression profiles. The amount of sample needed limits the use of small excision biopsies and/or needle biopsies from human or animal tissues. Linear amplification techniques have been developed to increase the amount of sample derived cDNA. These amplified samples can be hybridised on microarrays. However, little information is available whether microarrays based on amplified and unamplified material yield comparable results. In the present study we compared microarray data obtained from amplified mRNA derived from biopsies of rat cardiac left ventricle and non-amplified mRNA derived from the same organ. Biopsies were linearly amplified to acquire enough material for a microarray experiment. Both amplified and unamplified samples were hybridized to the Rat Expression Set 230 Array of Affymetrix. RESULTS: Analysis of the microarray data showed that unamplified material of two different left ventricles had 99.6% identical gene expression. Gene expression patterns of two biopsies obtained from the same parental organ were 96.3% identical. Similarly, gene expression pattern of two biopsies from dissimilar organs were 92.8% identical to each other.Twenty-one percent of reporters called present in parental left ventricular tissue disappeared after amplification in the biopsies. Those reporters were predominantly seen in the low intensity range. Sequence analysis showed that reporters that disappeared after amplification had a GC-content of 53.7+/-4.0%, while reporters called present in biopsy- and whole LV-samples had an average GC content of 47.8+/-5.5% (P <0.001). Those reporters were also predicted to form significantly more (0.76+/-0.07 versus 0.38+/-0.1) and longer (9.4+/-0.3 versus 8.4+/-0.4) hairpins as compared to representative control reporters present before and after amplification. CONCLUSION: This study establishes that the gene expression profile obtained after amplification of mRNA of left ventricular biopsies is representative for the whole left ventricle of the rat heart. However, specific gene transcripts present in parental tissues were undetectable in the minute left ventricular biopsies. Transcripts that were lost due to the amplification process were not randomly distributed, but had higher GC-content and hairpins in the sequence and were mainly found in the lower intensity range which includes many transcription factors from specific signalling pathways.

Animals↗

PubMed2006

Characterization of ovine hepatic gene expression profiles in response to Escherichia coli lipopolysaccharide using a bovine cDNA microarray.

BACKGROUND: During systemic gram-negative bacterial infections, lipopolysaccharide (LPS) ligation to the hepatic Toll-like receptor-4 complex induces the production of hepatic acute phase proteins that are involved in the host response to infection and limit the associated inflammatory process. Identifying the genes that regulate this hepatic response to LPS in ruminants may provide insight into the pathogenesis of bacterial diseases and eventually facilitate breeding of more disease resistant animals. The objective of this research was to profile the expression of ovine hepatic genes in response to Escherichia coli LPS challenge (0, 200, 400 ng/kg) using a bovine cDNA microarray and quantitative real-time PCR (qRT-PCR). RESULTS: Twelve yearling ewes were challenged iv with E. coli LPS (0, 200, 400 ng/kg) and liver biopsies were collected 4-5 hours post-challenge to assess hepatic gene expression profiles by bovine cDNA microarray and qRT-PCR analyses. The expression of CD14, C3, IL12R, NRAMP1, SOD and IGFBP3 genes was down regulated, whereas the expression of ACTHR, IFNalphaR, CD1, MCP-1 and GH was increased during LPS challenge. With the exception of C3, qRT-PCR analysis of 7 of these genes confirmed the microarray results and demonstrated that GAPDH is not a suitable housekeeping gene in LPS challenged sheep. CONCLUSION: We have identified several potentially important genes by bovine cDNA microarray and qRT-PCR analyses that are differentially expressed during the ovine hepatic response to systemic LPS challenge. Their potential role in regulating the inflammatory response to LPS warrants further investigation.

Animals↗

PubMed2003

Transcriptional silencing of zinc finger protein 185 identified by expression profiling is associated with prostate cancer progression.

We profiled the expression of genes in benign and untreated human prostate cancer tissues using oligonucleotide microarrays. We report here 50 genes with distinct expression patterns in metastatic and confined tumors (Gleason score 6 and 9; lymph node invasive and noninvasive). Validation of expression profiles of 6 genes by quantitative PCR revealed a strong inverse correlation in the expression of zinc finger protein 185 (ZNF185), bullous pemphigoid antigen gene (BPAG1), and prostate secretory protein (PSP94) with progression of prostate cancer. Treatment of prostate cancer cell lines with 5-aza-2'-deoxycytidine (5-Aza-CdR), an inhibitor of DNA methylation, restored ZNF185 expression levels. Moreover, methylation-specific PCR confirmed methylation of the 5'CpG islands of the ZNF185 gene in all of the metastatic tissues and 44% of the localized tumor tissues, as well as in the prostate cancer cell lines tested. Thus, transcriptional silencing of ZNF185 by methylation in prostate tumor tissues implicates the ZNF185 gene in prostate tumorigenesis.

Aged↗

PubMed2005

Phenotypic anchoring of global gene expression profiles induced by N-hydroxy-4-acetylaminobiphenyl and benzo[a]pyrene diol epoxide reveals correlations between expression profiles and mechanism of toxicity.

The goal of this study was to compare changes in gene expression induced by exposure to different carcinogens and to anchor these changes to the induced levels of toxicity and mutagenesis. The human TK6 lymphoblastoid cell line was used as an in vitro model system, and reactive metabolites of two human carcinogens, benzo[a]pyrene and 4-aminobiphenyl, were used as model compounds. We first determined the toxicity of the model compounds N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) and benzo[a]pyrene diol epoxide (BPDE) in TK6 cells. BPDE was about 1000-fold more toxic and mutagenic than N-OH-AABP in TK6 cells on a molar basis. We next treated cells with three doses of each compound that resulted in low, medium, and high toxicities (5, 15, and 40%) and harvested cells at different times after exposure. Using comparable levels of toxicity as the phenotypic anchor, we compared the patterns of gene expression induced by each reactive metabolite using printed cDNA microarrays comprising approximately 18,000 human gene/EST sequences. The microarray data from the N-OH-AABP and BPDE treatment groups were compared using self-organizing map clustering algorithms, as well as a statistical regression modeling approach. While subsets of genes indicative of a generalized stress response [Hsp 40 homologue (DNAJ), Hsp70, Hsp105, and Hsp 125] were detected after exposure to both compounds at all concentrations, there were also many differentially regulated genes, including phase I xenobiotic metabolism [e.g., glutathione transferase omega (GSTTLp28) and antioxidant enzymes (Apxl)]. Other differentially regulated genes included those encoding proteins involved in all major DNA repair pathways, including excision repair (e.g., ERCC5), mismatch repair (e.g., MLH3), damage specific DNA binding protein (e.g., DDB2), and cisplatin resistance-associated overexpressed protein (LUC7A, CRA). Differences in the transcriptional response of TK6 cells to N-OH-AABP or BPDE exposure may explain the dramatic differences in the toxicity and mutagenicity of these human carcinogens.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed2003

Gene expression profiling in ecotoxicology.

Gene expression profiling is a powerful new end point for ecotoxicology and a means for bringing the genomics revolution to this field. We review the usefulness of gene expression profiling as an end point in ecotoxicology and describe methods for applying this approach to non-model organisms. Since genomes contain thousands of genes representing hundreds of pathways, it is possible to identify toxicant-specific responses from this wide array of possibilities. Stressor-specific signatures in gene expression profiles can be used to diagnose which stressors are impacting populations in the field. Screening for stress-induced genes requires special techniques in organisms without sequenced genomes. These techniques include differential display polymerase chain reaction (DD PCR), suppressive subtractive hybridization PCR (SSH PCR), and representational difference analysis. Gene expression profiling in model organisms like yeast has identified hundreds of genes that are up-regulated in response to various stressors, including several that are well characterized (e.g., hsp78, metallothionein, superoxide dismutase). Using consensus PCR primers from several animal sequences, it is possible to amplify some of these well characterized stress-induced genes from organisms of interest in ecotoxicology. We describe how several stress-induced genes can be grouped into cDNA arrays for rapidly screening samples.

Animals↗

PubMed2004

Microarray gene expression profiling and analysis in renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is the most common cancer in adult kidney. The accuracy of current diagnosis and prognosis of the disease and the effectiveness of the treatment for the disease are limited by the poor understanding of the disease at the molecular level. To better understand the genetics and biology of RCC, we profiled the expression of 7,129 genes in both clear cell RCC tissue and cell lines using oligonucleotide arrays. METHODS: Total RNAs isolated from renal cell tumors, adjacent normal tissue and metastatic RCC cell lines were hybridized to affymatrix HuFL oligonucleotide arrays. Genes were categorized into different functional groups based on the description of the Gene Ontology Consortium and analyzed based on the gene expression levels. Gene expression profiles of the tissue and cell line samples were visualized and classified by singular value decomposition. Reverse transcription polymerase chain reaction was performed to confirm the expression alterations of selected genes in RCC. RESULTS: Selected genes were annotated based on biological processes and clustered into functional groups. The expression levels of genes in each group were also analyzed. Seventy-four commonly differentially expressed genes with more than five-fold changes in RCC tissues were identified. The expression alterations of selected genes from these seventy-four genes were further verified using reverse transcription polymerase chain reaction (RT-PCR). Detailed comparison of gene expression patterns in RCC tissue and RCC cell lines shows significant differences between the two types of samples, but many important expression patterns were preserved. CONCLUSIONS: This is one of the initial studies that examine the functional ontology of a large number of genes in RCC. Extensive annotation, clustering and analysis of a large number of genes based on the gene functional ontology revealed many interesting gene expression patterns in RCC. Most notably, genes involved in cell adhesion were dominantly up-regulated whereas genes involved in transport were dominantly down-regulated. This study reveals significant gene expression alterations in key biological pathways and provides potential insights into understanding the molecular mechanism of renal cell carcinogenesis.

Adenocarcinoma, Clear Cell↗

PubMed2005

Gene function classification using NCI-60 cell line gene expression profiles.

Gene expression patterns from NCI's panel of 60 cell lines were used to train a Neural Network model for classifying genes to pathways. The model assigns probabilities to each gene for each of the 21 modeled pathways assigned by the Kyoto Encyclopedia of Genes and Genomes. Cross-validation of the model showed that 10 of the 21 pathways exhibited good performance in statistical significance and accuracy. The model was designed to output gene probabilities that could be screened for higher probabilities resulting in higher confidence in classification though yielding fewer genes per pathway. The model was deployed on 5798 genes and our approach allowed us to ascertain the most relevant genes above an estimated background. Eight pathways were identified with both good cross-validation and significant numbers above background, TCA Cycle, Oxidative Phosphorylation, Porphyrin Biosynthesis, Ribosome, Polymerases, Proteasome, Cell Cycle, and Cell Adhesion. Gene Ontology (GO) annotation was used for additional validation of gene classification results. A total of 551 GO annotated genes and 468 unannotated genes were classified to the 8 pathways. The primary and secondary classifications of genes revealed known pathway relationships and provide the potential for discovering new pathway relationships.

Cell Line↗

PubMed2003

Evaluation of techniques using amplified nucleic acid probes for gene expression profiling.

Gene expression analyses using spotted cDNA microarrays typically require relatively large quantities of total RNA (up to 100 microg) or polyA+RNA (1-5 microg). However, samples obtained by microdissection, patient biopsies, or embryonic samples often are small and yield an insufficient amount of RNA. Methods such as linear RNA amplification by in vitro transcription (IVT) or cDNA amplification by PCR are currently being used to circumvent these limitations. In the present study, labeled probes from mouse liver and kidney were generated with two amplification methods and were analyzed in terms of reproducibility of intensity values from repeated experiments. In addition, the reliability of differential gene expression detection among the different types of amplified and non-amplified probes was assessed. Data derived from IVT-amplified RNA, as well as from PCR-amplified cDNA probes were reproducible with correlation coefficients of 0.89 and 0.91, respectively. 88-92% of the strongly differentially expressed genes detected with non-amplified probes were also detected as being at least two-folds differentially expressed with the amplified probes. Both the PCR-amplified probe and the IVT-amplified probe were comparable in reproducibility and reliability.

Animals↗

PubMed2006

Identification and expression profiling of 10 novel spermatid expressed CYPT genes.

To identify candidate genes for poor sperm morphology, we have screened for genes expressed during spermiogenesis. We identified 10 new members of the cysteine-rich perinuclear theca (CYPT) family showing that this family contains at least 15 members, which also includes the casein kinase II target genes. Based on similarity the CYPT sequences could be divided into two groups, Cypt1-10 and the novel members Cypt12-15. The 5'-end of the CYPT family is highly similar to exon1A and part of the first intron of Zfy2. Seven CYPT genes mapped to the X chromosome; six contained an intron and one was intron-less. One CYPT gene mapped to chromosome 3 and one mapped to chromosome 9 which were both intron-less. The upstream region of the CYPT family and Zfy2 genes is conserved. For some the conservation extended over a large region, however, only about 150 nucleotides is conserved among all CYPT members and Zfy2. Nevertheless, the short conserved promoter leads to essentially identical expression profiles for the CYPT family members and Zfy2, which was clearly different from the profile of Zfy1. Expression of the CYPT family and Zfy2 preceded the expression of other spermatid-specific genes such as the transition proteins and the protamines. In situ hybridization revealed a low expression in pachytene spermatocytes from stages IX-X followed by a strong upregulation in spermatids from stage VI with maximum expression in spermatids in stages VII-VIII. The CYPT family may function in the remodeling of the spermatid nucleus before condensation of the DNA.

Animals↗

PubMed2001

Growth and gene expression profile analyses of endometrial cancer cells expressing exogenous PTEN.

The PTEN tumor suppressor gene encodes a multifunctional phosphatase that plays an important role in inhibiting the phosphatidylinositol-3-kinase pathway and downstream functions that include activation of Akt/protein kinase B, cell survival, and cell proliferation. Enforced expression of PTEN in various cancer cell lines decreases cell proliferation through arrest of the cell cycle, accompanied in some cases by induction of apoptosis. We used cDNA microarrays containing 4009 cDNAs to examine changes in gene-expression profiles when exogenous PTEN was induced in PTEN-defective cells. The microarrays and subsequent semi-quantitative reverse transcription-PCR analysis revealed transcriptional stimulation of 99 genes and repression of 72 genes. Some of the differentially expressed genes already had been implicated in cell proliferation, differentiation, apoptosis, or cell cycle control, e.g., overexpression of PTEN-induced transactivation of cyclin-dependent inhibitor 1B (p27Kip1) and 2B (p15INK4B), members of the TNF receptor family, tumor necrosis factor-associated genes, and members of the Notch-signaling and Mad families. To our knowledge this is the first report of transactivation of those genes by PTEN. The genes differentially expressed in our experiments also included many whose correlation with cancer development had not been recognized before. Our data should contribute to a greater understanding of the broad spectrum of ways in which PTEN affects intracellular signaling pathways. Analysis of expression profiles with microarrays appears to be a powerful approach for identifying anticancer genes and/or disease-specific targets for cancer therapy.

Adenoviridae↗

PubMed2004

Expression profiling of metalloproteinases and their inhibitors in cartilage.

OBJECTIVE: To profile the expression of all known members of the matrix metalloproteinase (MMP), ADAMTS, and tissue inhibitor of metalloproteinases (TIMP) gene families in normal cartilage and cartilage from patients with osteoarthritis (OA). METHODS: Human cartilage was obtained from femoral heads at joint replacement for OA or following fracture to the femoral neck. Total RNA was purified, and gene expression was assayed using quantitative real-time polymerase chain reaction. RESULTS: Several members of the above gene families were regulated in OA. Genes that showed increased expression in OA were MMP13, MMP28, and ADAMTS16 (all at P < 0.001), MMP9, MMP16, ADAMTS2, and ADAMTS14 (all at P < 0.01), and MMP2, TIMP3, and ADAMTS12 (all at P < 0.05). Genes with decreased expression in OA were MMP1, MMP3, and ADAMTS1 (all at P < 0.001), MMP10, TIMP1, and ADAMTS9 (all at P < 0.01), and TIMP4, ADAMTS5, and ADAMTS15 (all at P < 0.05). Correlation analysis revealed that groups of genes across the gene families were coexpressed in cartilage. CONCLUSION: This is the first comprehensive expression profile of all known MMP, ADAMTS, and TIMP genes in cartilage. Elucidation of patterns of expression provides a foundation with which to understand mechanisms of gene regulation in OA and potentially to refine the specificity of antiproteolytic therapies.

ADAM Proteins↗

PubMed2002

Gene expression profiling: methodological challenges, results, and prospects for addiction research.

This review describes the current methods used to profile gene expression. These methods include microarrays, spotted arrays, serial analysis of gene expression (SAGE), and massive parallel signature sequencing (MPSS). Methodological and statistical problems in interpreting microarray and spotted array experiments are also discussed. Methods and formats such as minimum information about microarray experiments (MIAME) needed to share gene expression data are described. The last part of the review provides an overview of the application of gene-expression profiling technology to substance abuse research and discusses future directions.

Animals↗

PubMed2004

Gene expression profiling of Escherichia coli expressing double Vitreoscilla haemoglobin.

In a recent investigation, expression of a double Vitreoscilla haemoglobin (two fused VHb molecules) in Escherichia coli grown in shake flasks resulted in higher final cell density and considerably higher levels of ribosomes and tRNA. In this study, we have investigated the E. coli transcriptome in cells expressing native VHb, double VHb and control cells lacking VHb by hybridising mRNA from the different constructs to high-density oligonucleotide arrays. Within the 95% confidence interval, 4 and 5% of all detected genes in native VHb cells were up- and down-regulated, respectively; in double VHb cells the corresponding numbers were 6 and 10%, respectively. Dividing the data into different functional groups revealed that genes involved in energy metabolism, central intermediary metabolism and cell processes were the most affected at the mRNA level. Particularly, the up-regulation of genes involved in translation and posttranslational modification observed in double VHb cells demonstrates a strong relationship between the regulation of ribosomal genes and the actual number of ribosomes.

Bacterial Proteins↗

PubMed2006

Gene expression profiling of differentiating embryonic stem cells expressing dominant negative fibroblast growth factor receptor 2.

Embryonic stem (ES) cells are derived from the inner cell mass of the blastocyst and can be cultured as three-dimensional embryoid bodies (EBs) in which embryonic pregastrulation stages are faithfully mimicked. Fibroblast growth factor receptors (mainly FGFR2) are involved in the first differentiation events during early mammalian embryogenesis. It has been demonstrated that the presence of FGFR2 is a prerequisite for laminin-111 and collagen type IV synthesis and subsequently basement membrane formation in EBs. To identify genes that are influenced by FGFR signalling, we performed global gene expression profiling of differentiating EBs expressing dominant negative FGFR2 (dnFGFR2), acquiring an extensive catalogue of down- and up-regulated genes. We show a strong down-regulation of endodermal and basement membrane related genes, which strengthen the view that the FGFR signalling pathway is a main stimulator of basement membrane synthesis in EBs. We further present down-regulation of genes previously not linked to FGFR signalling, and in addition an active transcription of some mesodermal related genes in differentiating dnFGFR2 EBs.

Animals↗