scholarly journals Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas

2018 ◽  
Vol 178 (3) ◽  
pp. 295-307 ◽  
Author(s):  
Camilla Maria Falch ◽  
Arvind Y M Sundaram ◽  
Kristin Astrid Øystese ◽  
Kjersti Ringvoll Normann ◽  
Tove Lekva ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Growth ◽  
Epithelial Mesenchymal Transition ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Growth Potential ◽  
Mesenchymal Transition ◽  
Volume Doubling Time ◽  
Slow Growing

ObjectiveReliable biomarkers associated with aggressiveness of non-functioning gonadotroph adenomas (GAs) are lacking. As the growth of tumor remnants is highly variable, molecular markers for growth potential prediction are necessary. We hypothesized that fast- and slow-growing GAs present different gene expression profiles and reliable biomarkers for tumor growth potential could be identified, focusing on the specific role of epithelial-mesenchymal transition (EMT).Design and methodsEight GAs selected for RNA sequencing were equally divided into fast- and slow-growing group by the tumor volume doubling time (TVDT) median (27.75 months). Data were analyzed by tophat2, cufflinks and cummeRbund pipeline. 40 genes were selected for RT-qPCR validation in 20 GAs based on significance, fold-change and pathway analyses. The effect of silencingMTDH(metadherin) andEMCN(endomucin) onin vitromigration of human adenoma cells was evaluated.Results350 genes were significantly differentially expressed (282 genes upregulated and 68 downregulated in the fast group,P-adjusted <0.05). Among 40 selected genes, 11 showed associations with TVDT (−0.669<R<−0.46,P < 0.05). These werePCDH18, UNC5D, EMCN, MYO1B, GPM6Aand six EMT-related genes (SPAG9, SKIL, MTDH, HOOK1, CNOT6LandPRKACB).MTDH, but notEMCN, demonstrated involvement in cell migration and association with EMT markers.ConclusionsFast- and slow-growing GAs present different gene expression profiles, and genes related to EMT have higher expression in fast-growing tumors. In addition toMTDH, identified as an important contributor to aggressiveness, the other genes might represent markers for tumor growth potential and possible targets for drug therapy.

scholarly journals A COMPARATIVE ANALAYSIS OF INTER-SITE GENE EXPRESSION HETEROGENICITY OF NORMAL HUMAN BUCCAL MUCOSA WITH NORMAL GINGIVAL MUCOSA

2021 ◽  
Author(s):  
Rooban Thavarajah ◽  
Kannan Ranganathan
Keyword(s):  
Gene Expression ◽  
Buccal Mucosa ◽  
Epithelial Mesenchymal Transition ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Gene Expression Omnibus ◽  
Genotypic Difference ◽  
Mesenchymal Transition ◽  
Normal Human ◽  
The Difference

BACKGROUND: Description of heterogeneity of gene expression of various human intraoral sites are not adequate. The aim of this study was to explore the difference of gene expression profiles of whole tissue obtained from apparently normal human gingiva and buccal mucosa (HGM, HBM). MATERIALS AND METHODS: Gene sets fulfilling inclusion and exclusion criteria of HGM and HBM in gene Expression Omnibus(GEO) database were identified, segregated, filtered and analysed using the ExAtlas online web tool using pre-determined cut-off. The differentially expressed genes were studied for epithelial keratinization related, housekeeping(HKG), extracellular matrix related(ECMRG) and epithelial-mesenchymal transition related genes(EMTRGs). RESULTS: In all 40 HBM and 64 HGM formed the study group. In all there were 18012 significantly expressed genes. Of this, 1814 were over-expressed and 1862 under-expressed HBM genes as compared to HGM. One in five of all studied genes significantly differed between HBM and HGM. For the keratinization genes, 1 in 6 differed. One of every 5 HKG-proteomics genes differed between HBM and HGM, while this ratio was 1-in 4 for all ECMRGs and EMTRGs. DISCUSSION: This difference in the gene expression between the HBM and HGM could possibly influence a multitude of biological pathways. This result could explain partly the difference in clinicopathological features of oral lesions occurring in HBM and HGM. The innate genotypic difference between the two intra-oral niches could serve as confounding factor in genotypic studies. Hence studies that compare the HBM and HGM should factor-in these findings while evaluating their results.

Transcriptional profiling of the transition from normal intestinal epithelia to adenomas and carcinomas in the APCMin/+ mouse

2003 ◽  
Vol 15 (3) ◽  
pp. 228-235 ◽  
Author(s):  
Nicholas F. Paoni ◽  
Matthew W. Feldman ◽  
Linda S. Gutierrez ◽  
Victoria A. Ploplis ◽  
Francis J. Castellino
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Tumor Growth ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Transcript Abundance ◽  
Growth Potential ◽  
Negative Regulator ◽  
Insulin Like Growth Factor

Mutations in the adenomatous polyposis coli (APC) gene that result in excessive β-catenin-induced cell signaling are implicated in the risk of colon cancer. Although the mechanism of APC-mediated tumorigenesis is known, the pathways that translate β-catenin signaling into tumor growth in vivo are undefined. To address this, gene expression profiles of normal intestinal epithelial cells were compared with those from adenomas and carcinomas from APCMin/+ mice, a model of APC-related colorectal cancer. The gene expression profiles of adenomas and carcinomas were very similar, which is consistent with the theory that carcinomas progress from adenomas in this model system. Tumors had altered transcript abundance for members of several pathways that influence cell growth and proliferation including growth factors/receptors, molecules involved in apoptosis, and protein processing and catabolism enzymes. Comparison of gene expression between adenomas and carcinomas revealed nine differentially expressed transcripts. These included members of three growth-regulating pathways, and the results are consistent with the increased growth potential of carcinomas. SRY-box containing gene 17 (Sox 17), a negative regulator of β-catenin signaling, and calbindin-D9K, a factor that enhances calcium transport, were more highly expressed in adenomas than carcinomas (∼4-fold and 15- to 22-fold, respectively). Transcript abundance for insulin-like growth factor binding protein 5, which mediates insulin-like growth factor function, was 2.6-fold greater in carcinomas. Because the changes in gene expression observed in this study are directly associated with a deficiency in APC, the data provide new insights into how loss of this important tumor suppressor translates into benign and malignant tumor growth.

scholarly journals Transcriptome analysis of gravitational effects on mouse skeletal muscles under microgravity and artificial 1 g onboard environment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Risa Okada ◽  
Shin-ichiro Fujita ◽  
Riku Suzuki ◽  
Takuto Hayashi ◽  
Hirona Tsubouchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Transcriptome Analysis ◽  
Fiber Type ◽  
Expression Profiles ◽  
Space Station ◽  
Gene Expression Profiles

AbstractSpaceflight causes a decrease in skeletal muscle mass and strength. We set two murine experimental groups in orbit for 35 days aboard the International Space Station, under artificial earth-gravity (artificial 1 g; AG) and microgravity (μg; MG), to investigate whether artificial 1 g exposure prevents muscle atrophy at the molecular level. Our main findings indicated that AG onboard environment prevented changes under microgravity in soleus muscle not only in muscle mass and fiber type composition but also in the alteration of gene expression profiles. In particular, transcriptome analysis suggested that AG condition could prevent the alterations of some atrophy-related genes. We further screened novel candidate genes to reveal the muscle atrophy mechanism from these gene expression profiles. We suggest the potential role of Cacng1 in the atrophy of myotubes using in vitro and in vivo gene transductions. This critical project may accelerate the elucidation of muscle atrophy mechanisms.

Simulated microgravity using the Random Positioning Machine inhibits differentiation and alters gene expression profiles of 2T3 preosteoblasts

2005 ◽  
Vol 288 (6) ◽  
pp. C1211-C1221 ◽  
Author(s):  
Steven J. Pardo ◽  
Mamta J. Patel ◽  
Michelle C. Sykes ◽  
Manu O. Platt ◽  
Nolan L. Boyd ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alkaline Phosphatase ◽  
Bone Loss ◽  
Simulated Microgravity ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Underlying Mechanism ◽  
Bone Biology ◽  
Random Positioning Machine

Exposure to microgravity causes bone loss in humans, and the underlying mechanism is thought to be at least partially due to a decrease in bone formation by osteoblasts. In the present study, we examined the hypothesis that microgravity changes osteoblast gene expression profiles, resulting in bone loss. For this study, we developed an in vitro system that simulates microgravity using the Random Positioning Machine (RPM) to study the effects of microgravity on 2T3 preosteoblast cells grown in gas-permeable culture disks. Exposure of 2T3 cells to simulated microgravity using the RPM for up to 9 days significantly inhibited alkaline phosphatase activity, recapitulating a bone loss response that occurs in real microgravity conditions without altering cell proliferation and shape. Next, we performed DNA microarray analysis to determine the gene expression profile of 2T3 cells exposed to 3 days of simulated microgravity. Among 10,000 genes examined using the microarray, 88 were downregulated and 52 were upregulated significantly more than twofold using simulated microgravity compared with the static 1-g condition. We then verified the microarray data for some of the genes relevant in bone biology using real-time PCR assays and immunoblotting. We confirmed that microgravity downregulated levels of alkaline phosphatase, runt-related transcription factor 2, osteomodulin, and parathyroid hormone receptor 1 mRNA; upregulated cathepsin K mRNA; and did not significantly affect bone morphogenic protein 4 and cystatin C protein levels. The identification of gravisensitive genes provides useful insight that may lead to further hypotheses regarding their roles in not only microgravity-induced bone loss but also the general patient population with similar pathological conditions, such as osteoporosis.

171 THE EFFECT OF TRICHOSTATIN A ON THE DEVELOPMENT AND THE GLOBAL GENE EXPRESSION PATTERNS IN MOUSE EMBRYOS DEVELOPING IN VITRO

2008 ◽  
Vol 20 (1) ◽  
pp. 165
Author(s):  
X. S. Cui ◽  
X. Y. Li ◽  
T. Kim ◽  
N.-H. Kim
Keyword(s):  
Gene Expression ◽  
Trichostatin A ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Mouse Embryos ◽  
Differentially Expressed ◽  
Gene Expression Patterns ◽  
Cell Stage

Trichostatin A (TSA) is an inhibitor of histone deacetylase and is able to alter gene expression patterns by interfering with the removal of acetyl groups from histones. The aim of this study was to determine the effect of TSA treatment on the development and gene expression patterns of mouse zygotes developing in vitro. The addition of 100 nm TSA to the culture medium did not affect the cleavage of mouse embryos (TSA treatment, 148/150 (99%) v. control, 107/107 (100%)); however, embryos that were treated with TSA arrested at the 2-cell stage (145/148, 98%). We estimated the number of nuclei in control and TSA-treated embryos by propidium iodide staining, taking into account the presence of any cells with two or more nuclei. At 62–63 h post-hCG stimulation, control zygotes had developed to the 4-cell stage and exhibited one nucleus in each blastomere, indicative of normal development. In contrast, we observed tetraploid nuclei in at least one blastomere in 20.8% (11/53) of the embryos that had been treated with TSA. At 28–29 h post-hCG stimulation (metaphase of the 1-cell stage), there was no difference in the mitotic index (as determined by analyzing the microtubule configuration) in the TSA group compared to the control group. At the 2-cell stage, however, we did not observe mitotic spindles and metaphase chromatin in embryos in the TSA treatment group compared to the controls. Interestingly, when embryos were cultured in TSA-free medium from 35 h post-hCG stimulation (S- or early G2-phase of the 2-cell stage) onward, almost all of them (47/50) developed to the blastocyst stage. In contrast, when embryos were cultured in TSA-free medium from 42 h post-hCG stimulation (middle G2-phase of the 2-cell stage) onward, they did not develop to the 4-cell stage. We used Illumina microarray technology to analyze the gene expression profiles in control and TSA-treated late 2-cell-stage embryos. Applied Biosystems Expression System software was used to extract assay signals and assay signal-to-noise ratio values from the microarray images. Our data showed that 897 genes were significantly (P < 0.05; 2-sample t-test) up- or down-regulated by TSA treatment compared to controls. Analysis using the PANTHER classification system (https://panther.appliedbiosystems.com) revealed that the 575 genes that were differentially expressed in the TSA group compared to the control were classified as being associated with putative biological processes or molecular function. Overall, in terms of putative biological processes, more nucleoside, nucleotide, and nucleic acid metabolism, protein metabolism and modification, signal transduction, developmental process, and cell cycle genes were differentially expressed between the TSA and control groups. In terms of putative molecular function, more nucleic acid-binding transcription factor and transferase genes were differentially expressed between the groups. The results collectively suggest that inhibition of histone acetylation in mouse embryos affects gene expression profiles at the time of zygotic genome activation, and this subsequently affects further development.

scholarly journals A potent CBP/p300-Snail interaction inhibitor suppresses tumor growth and metastasis in wild-type p53-expressing cancer

2020 ◽  
Vol 6 (17) ◽  
pp. eaaw8500
Author(s):  
Hong-Mei Li ◽  
Yan-Ran Bi ◽  
Yang Li ◽  
Rong Fu ◽  
Wen-Cong Lv ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Effects ◽  
Creb Binding Protein ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Patients With Cancer ◽  
Wild Type P53

The zinc finger transcription factor Snail is aberrantly activated in many human cancers and associated with poor prognosis. Therefore, targeting Snail is expected to exert therapeutic benefit in patients with cancer. However, Snail has traditionally been considered “undruggable,” and no effective pharmacological inhibitors have been identified. Here, we found a small-molecule compound CYD19 that forms a high-affinity interaction with the evolutionarily conserved arginine-174 pocket of Snail protein. In aggressive cancer cells, CYD19 binds to Snail and thus disrupts Snail’s interaction with CREB-binding protein (CBP)/p300, which consequently impairs CBP/p300-mediated Snail acetylation and then promotes its degradation through the ubiquitin-proteasome pathway. Moreover, CYD19 restores Snail-dependent repression of wild-type p53, thus reducing tumor growth and survival in vitro and in vivo. In addition, CYD19 reverses Snail-mediated epithelial-mesenchymal transition (EMT) and impairs EMT-associated tumor invasion and metastasis. Our findings demonstrate that pharmacologically targeting Snail by CYD19 may exert potent therapeutic effects in patients with cancer.

Gene Expression Profiles in Rat Liver Slices Exposed to Hepatocarcinogenic Enzyme Inducers, Peroxisome Proliferators, and 17α-Ethinylestradiol

2006 ◽  
Vol 25 (5) ◽  
pp. 379-395 ◽  
Author(s):  
Gisela Werle-Schneider ◽  
Andreas Wölfelschneider ◽  
Marie Charlotte von Brevern ◽  
Julia Scheel ◽  
Thorsten Storck ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rat Liver ◽  
Mode Of Action ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Peroxisome Proliferators ◽  
Liver Slices ◽  
Enzyme Inducers

Transcription profiling is used as an in vivo method for predicting the mode-of-action class of nongenotoxic carcinogens. To set up a reliable in vitro short-term test system DNA microarray technology was combined with rat liver slices. Seven compounds known to act as tumor promoters were selected, which included the enzyme inducers phenobarbital, α-hexachlorocyclohexane, and cyproterone acetate; the peroxisome proliferators WY-14,643, dehydroepiandrosterone, and ciprofibrate; and the hormone 17 α-ethinylestradiol. Rat liver slices were exposed to various concentrations of the compounds for 24 h. Toxicology-focused TOXaminer™ DNA microarrays containing approximately 1500 genes were used for generating gene expression profiles for each of the test compound. Hierarchical cluster analysis revealed that (i) gene expression profiles generated in rat liver slices in vitro were specific allowing classification of compounds with similar mode of action and (ii) expression profiles of rat liver slices exposed in vitro correlate with those induced after in vivo treatment (reported previously). Enzyme inducers and peroxisome proliferators formed two separate clusters, confirming that they act through different mechanisms. Expression profiles of the hormone 17 α-ethinylestradiol were not similar to any of the other compounds. In conclusion, gene expression profiles induced by compounds that act via similar mechanisms showed common effects on transcription upon treatment in vivo and in rat liver slices in vitro.

MLL-AF9 and MLL-ENL Induce Deregulation of Similar Downstream Candidate Genes: An Analysis across Experimental Protocols and Laboratories.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3372-3372
Author(s):  
Ashish R. Kumar ◽  
Robert K. Slany ◽  
Jay L. Hess ◽  
John H. Kersey
Keyword(s):  
Gene Expression ◽  
Fusion Protein ◽  
Fusion Gene ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Expression Systems ◽  
Rt Pcr ◽  
Conditional Expression

Expression profiling has become an important tool for understanding gene deregulation in MLL-fusion leukemias. However, the results of gene profiling experiments are difficult to interpret when applied to leukemia cells because (i) leukemias arise in cells that differ greatly in their gene expression profiles, and (ii) leukemias most often require secondary genetic events in addition to the MLL fusion gene. Two principal model systems have been used to understand the direct effects of MLL-fusion genes. Knock-in models have the advantage of the fusion gene being under control of the physiologic promoter. On the other hand, conditional expression systems offer the ability to conduct short term experiments, permitting the analysis of direct effects on downstream genes. In the present combined-analysis, we used the Affymetrix U74Av2 oligonucleotide microarray to evaluate the effects of the MLL-fusion gene in vivo and in vitro respectively using two closely related MLL fusion genes - MLL-AF9 for knock-in and MLL-ENL for conditional expression. In the MLL-AF9 study, we compared gene expression profiles of bone marrow cells from MLL-AF9 knock-in mice (C57Bl/6, MLL-AF9+/−) to those of age-matched wild type mice (Kumar et. al. 2004, Blood). We used a t-test (p<0.05) to selected genes that showed significant changes in expression levels. In the MLL-ENL study, we transformed murine primary hematopoietic cells with a conditional MLL-ENL vector (MLL-ENL fused to the modified ligand-binding domain of the estrogen receptor) such that the fusion protein was active only in the presence of tamoxifen. We then studied the downstream effects of the fusion protein by comparing gene expression profiles of the cells in the presence and absence of tamoxifen. We used a pair-wise comparison analysis to select genes that showed a change in expression level of 1.5 fold or greater in at least two of three experiments (Zeisig et. al. 2004, Mol. Cell Biol.). Those genes that were up-regulated in both datasets were then compiled together. This list included Hoxa7, Hoxa9 and Meis1. The results for these 3 genes were confirmed by quantitative RT-PCR in both the MLL-AF9-knock-in and the MLL-ENL-conditional-expression systems. The remaining candidate genes in the common up-regulated gene set (not yet tested by quantitative RT-PCR) include protein kinases (Bmx, Mapk3, Prkcabp, Acvrl1, Cask), RAS-associated proteins (Rab7, Rab3b), signal transduction proteins (Notch1, Eat2, Shd, Fpr1), cell membrane proteins (Igsf4), chaperones (Hsp70.2), transcription factors (Isgf3g), proteins with unknown functions (Olfm1, Flot1), and hypothetical proteins. The results of the combined analysis demonstrate that these over-expressions are (i) a direct and sustained effect of the MLL-fusion protein, (ii) are independent of secondary events that might be involved in leukemogensis, and (iii) are independent of the two partner genes that participate in these fusions. The over-expression of a few genes in both the -in vitro and in vivo experimental systems makes these molecules very interesting for further studies, to understand the biology of MLL-fusion leukemias and for development of new therapeutic strategies.

Overexpression of BRE in Pediatric MLL-Rearranged Acute Myeloid Leukemia Associated with t(9;11)(p22;q23).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3471-3471
Author(s):  
Brian Balgobind ◽  
C. Michel Zwaan ◽  
Susan T.C.J.M. Arentsen-Peters ◽  
Dirk Reinhardt ◽  
Ursula Creutzig ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Apoptotic Effect ◽  
The Mean ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Abstract 3471 Poster Board III-359 One important cytogenetic subgroup of pediatric acute myeloid leukemia (AML) is characterized by translocations of chromosome 11q23, which accounts for 15 to 20% of all cases with an evaluable chromosome analysis. In most of these cases, the mixed lineage leukemia (MLL) gene is involved. More than 50 fusion translocation partners of the MLL gene have been identified and outcome differs by translocation partner, suggesting differences in the biological background. So far these biological differences have not been unravelled. Therefore, we investigated the gene expression profiles of MLL-rearranged subgroups in pediatric AML in order to discover and identify the role of differentially expressed genes. Affymetrix Human Genome U133 plus 2.0 microarrays were used to generate gene expression profiles of 257 pediatric AML cases, which included 21 pediatric AML cases with t(9;11)(p22;q23) and 33 with other MLL-rearrangements. With these profiles, we were able to identify a specific gene expression signature for t(9;11)(p22;q23) using an empirical Bayes linear regression model (Bioconductor package: Limma). This signature was mainly determined by overexpression of the BRE (brain and reproductive organ-expressed) gene. The mean average VSN normalized expression for BRE in the t(9;11)(p22;q23) subgroup was 3.7-fold higher compared with that in other MLL-rearranged cases (p<0.001). Validation by RQ-PCR confirmed this higher expression in t(9;11)(p22;q23) cases (p<0.001). In addition, we confirmed that overexpression of BRE was predominantly found in t(9;11)(p22;q23) in an independent gene expression profile cohort (Ross et al, Blood 2002). Remarkably, MLL-rearranged cases with a BRE expression higher than the mean expression showed a significant better 3 year disease free survival than MLL-rearranged cases with a lower expression (80±13% vs. 30±10%, p=0.02). Previously, overexpression of BRE has been described in hepatocellular carcinomas (HCC) (Chang et al., Oncogene 2008) and an anti-apoptotic effect was described. We transfected BRE in the monomac-1 cell line, which harbors a t(9;11)(p22;q23). We did not find a proliferative advantage for BRE overexpression using a BrDU-assay nor changes in drug sensitivity, indicating that the anti-apoptotic effect as described for HCC in vivo could not be confirmed in vitro in AML. In conclusion, overexpression of the BRE gene is predominantly involved in pediatric MLL-rearranged AML with t(9;11)(p22;q23). Moreover, high expression of BRE showed a favorable prognosis. We did not find any influence of BRE expression on cell proliferation or apoptosis in vitro. This indicates that further studies involving the role of the MLL-fusion protein on BRE transcription are necessary to unravel the leukemogenic role in pediatric AML. Disclosures No relevant conflicts of interest to declare.

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