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Acetaminophen-NAPQI Hepatotoxicity: A Cell Line Model System Genome-Wide Association Study

TOXICOLOGICAL SCIENCES 2011年第1期120卷 33-41页

作者： Moyer, Ann M. Fridley, Brooke L. Jenkins, Gregory D. Batzler, Anthony J. Pelleymounter, Linda L. Kalari, Krishna R. Ji, Yuan Chai, Yubo Nordgren, Kendra K. S. Weinshilboum, Richard M. Mayo Clin Dept Mol Pharmacol & Expt Therapeut Div Clin Pharmacol Rochester MN 55905 USA Mayo Clin Dept Hlth Sci Res Rochester MN 55905 USA

Acetaminophen is the leading cause of acute hepatic failure in many developed nations. Acetaminophen hepatotoxicity is mediated by the reactive metabolite N-acetyl-p-benzoquinonimine (NAPQI). We performed a "discovery" genome-wide association study using a cell line-based model system to study the possible contribution of genomics to NAPQI-induced cytotoxicity. A total of 176 lymphoblastoid cell lines from healthy subjects were treated with increasing concentrations of NAPQI. Inhibiting concentration 50 values were determined and were associated with "glutathione pathway" gene single nucleotide polymorphisms (SNPs) and genome-wide basal messenger RNA expression, as well as with 1.3 million genome-wide SNPs. A group of SNPs in linkage disequilibrium on chromosome 3 was highly associated with NAPQI toxicity. The p value for rs2880961, the SNP with the lowest p value, was 1.88 x 10(-7). This group of SNPs mapped to a "gene desert," but chromatin immunoprecipitation assays demonstrated binding of several transcription factor proteins including heat shock factor 1 (HSF1) and HSF2, at or near rs2880961. These chromosome 3 SNPs were not significantly associated with variation in basal expression for any of the genome-wide genes represented on the Affymetrix U133 Plus 2.0 GeneChip. We have used a cell line-based model system to identify a SNP signal associated with NAPQI cytotoxicity. If these observations are validated in future clinical studies, this SNP signal might represent a potential biomarker for risk of acetaminophen hepatotoxicity. The mechanisms responsible for this association remain unclear.

关键词： acetaminophen N-acetyl-p-benzoquinonimine NAPQI cytotoxicity single nucleotide polymorphisms SNPs expression array mRNA Human Variation Panel GWAS

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Identification of the bleomycin hydrolase gene as a methylated tumor suppressor gene in hepatocellular carcinoma using a novel triple-combination array method

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CANCER LETTERS 2011年第2期312卷 150-157页

作者： Okamura, Yukiyasu Nomoto, Shuji Hayashi, Masamichi Hishida, Mitsuhiro Nishikawa, Yoko Yamada, Suguru Fujii, Tsutomu Sugimoto, Hiroyuki Takeda, Shin Kodera, Yasuhiro Nakao, Akimasa Nagoya Univ Dept Surg 2 Grad Sch & Med Showa Ku Nagoya Aichi 4668550 Japan

In the present study, we sought to identify novel suppressor genes of hepatocellular carcinoma (HCC) using our newly designed triple-combination array. Using this method, the bleomycin hydrolase gene (BLMH) was detected as a candidate suppressor gene. We found that 28 of 48 (58.3%) tumor tissues showed BLMH promoter hypermethylation, and its expression level was significantly reduced in tumor tissues (P = 0.001). The present study suggests that our new method can detect novel genes of interest and that BLMH is a suppressor gene in HCC. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

关键词： Hepatocellular carcinoma Bleomycin hydrolase Tumor suppressor gene expression array Single nucleotide polymorphism array Methylation array

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A chronic obstructive pulmonary disease related signature in squamous cell lung cancer

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LUNG CANCER 2011年第2期72卷 177-183页

作者： Boelens, Mirjam C. Gustafson, Adam M. Postma, Dirkje S. Kok, Klaas van der Vries, Gerben van der Vlies, Pieter Spira, Avrum Lenburg, Marc E. Geerlings, Marie Sietsma, Hannie Timens, Wim van den Berg, Anke Groen, Harry J. M. Univ Groningen Dept Pulmonol Univ Med Ctr Groningen Groningen Netherlands Univ Groningen Univ Med Ctr Groningen Dept Pathol Groningen Netherlands Boston Univ Sch Med Ctr Pulm Boston MA 02118 USA Univ Groningen Dept Genet Univ Med Ctr Groningen Groningen Netherlands

The epidemiological relationship between squamous cell lung cancer (SCC) and chronic obstructive pulmonary disease (COPD), both smoking-related diseases, suggests that they have also a genetic basis. We compared 35 SCC patients with and without COPD with whole-genome gene expression profiles of laser microdissected tissue. Validation of differential expression was performed for 25 genes using quantitative (q)RT-PCR. Subsequently, we performed array-based CGH on the same tumor samples. We found that 374 probes were differentially expressed in SCC from patients with and without COPD. Forty-four probes were derived from genes with mitochondrial functions and 34 probes were located on 5q. All these probes showed a lower expression level in SCC from non-COPD patients. For a random selection of 25 mitochondrial and 5q genes, we confirmed the differential expression by qRT-PCR. Loss of 3p, 5q and 9p was observed, via array-CGH, to be more frequent in SCC from non-COPD patients as compared to SCC from COPD patients. Combination of chromosomal aberrations and the location of the differentially expressed genes showed significant association for loss of the 5q31.2-31.3 region and reduced expression of the 5q genes. In conclusion, a more frequent loss of 5q and a low expression of genes located on 5q in SCC tumors of non-COPD patients compared to tumors from COPD patients was identified suggesting that different oncogenetic pathways are operational in patients with and without COPD. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

关键词： Squamous cell lung carcinoma COPD expression array array-CGH

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cDNA-based transcript analysis of autologous eutopic and ectopic endometrium of women with moderate and severe endometriosis

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JOURNAL OF ENDOMETRIOSIS AND PELVIC PAIN DISORDERS 2011年第1期3卷 8-33页

作者： Khan, Meraj A. Sengupta, Jayasree Giudice, Linda C. Mittal, Suneeta Kumar, Sunesh Gupta, Siddharth Datta Sharma, Raju Najwa, Abdur Rashid Ghosh, Debabrata All India Inst Med Sci Dept Physiol New Delhi 110029 India Univ Calif San Francisco Dept Obstet Gynecol & Reprod Sci San Francisco CA USA All India Inst Med Sci Dept Obstet & Gynecol New Delhi India All India Inst Med Sci Dept Pathol New Delhi India All India Inst Med Sci Dept Radiodiag New Delhi India

Purpose: To explore differential gene expression between autologous eutopic and ectopic endometrium and the effect of phases, infertility, and severity of disease on this. Methods: cDNA arrays followed by post hoc analysis for 1190 selected human genes were performed to analyze transcript expression in autologous eutopic and ectopic endometrial samples obtained from 6 proven fertile and 4 subfertile volunteers with endometriosis (stage 3: n=5;stage 4: n=5) during either the proliferative (n=7) or secretory (n= 3) phase. Results: cDNA-based expression array analysis appeared sensitive, precise, and reliable in unsupervised analysis and quantitative RT-PCR. Sample clustering analysis revealed maximal cluster coefficient (C=0.8) between eutopic and ectopic clusters for all pairs, followed by that yielded by phases of cycle (C=0.6);fertility history (C=0.3), and stages of severity (C=0.3) had marginal effects. Of 42 genes showing differential regulation in pooled analysis, 3 genes (CAGA, MT2A, and VIM) were up-regulated and 39 genes including EPHA2, FOXM1, HPSE, ITGA5, ITGAE, ITGB3, PAEP, and TGFBR1 were down-regulated in ectopic endometrium. The high transcript number of AFP, ALOX15, F2RL1, and PRKCG in proliferative phase eutopic endometrium appears to be a potential biomarker for endometriosis. Conclusions: Differential expression of specific genes appeared as distinguishing features for ectopic endometrium compared with eutopic endometrium;many of them might be associated with poor cellular integrity of endometriotic cells. However, ectopic endometrium did not show overt molecular indication of tumorigenic potential.

关键词： Differential gene expression Endometriosis expression array

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Genome-wide analysis of Ollier disease: Is it all in the genes?

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ORPHANET JOURNAL OF RARE DISEASES 2011年第1期6卷 2-2页

作者： Pansuriya, Twinkal C. Oosting, Jan Krenacs, Tibor Taminiau, Antonie H. M. Verdegaal, Suzan H. M. Sangiorgi, Luca Sciot, Raf Hogendoorn, Pancras C. W. Szuhai, Karoly Bovee, Judith V. M. G. Leiden Univ Dept Pathol Med Ctr Leiden Netherlands Semmelweis Univ Dept Pathol & Expt Canc Res H-1085 Budapest Hungary Leiden Univ Med Ctr Dept Orthopaed Surg Leiden Netherlands Rizzoli Orthoped Inst Dept Med Genet Bologna Italy Katholieke Univ Leuven Dept Pathol Leuven Belgium Leiden Univ Med Ctr Dept Mol Cell Biol Leiden Netherlands

Background: Ollier disease is a rare, non-hereditary disorder which is characterized by the presence of multiple enchondromas (ECs), benign cartilaginous neoplasms arising within the medulla of the bone, with an asymmetric distribution. The risk of malignant transformation towards central chondrosarcoma (CS) is increased up to 35%. The aetiology of Ollier disease is unknown. Methods: We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis using Affymetrix SNP 6.0 array on 37 tumours of 28 Ollier patients in combination with expression array using Illumina Beadarray v3.0 for 7 ECs of 6 patients. Results: Non-recurrent EC specific copy number alterations were found at FAM86D, PRKG1 and ANKS1B. LOH with copy number loss of chromosome 6 was found in two ECs from two unrelated Ollier patients. One of these patients also had LOH at chromosome 3. However, no common genomic alterations were found for all ECs. Using an integration approach of SNP and expression array we identified loss as well as down regulation of POU5F1 and gain as well as up regulation of NIPBL. None of these candidate regions were affected in more than two Ollier patients suggesting these changes to be random secondary events in EC development. An increased number of genetic alterations and LOH were found in Ollier CS which mainly involves chromosomes 9p, 6q, 5q and 3p. Conclusions: We present the first genome-wide analysis of the largest international series of Ollier ECs and CS reported so far and demonstrate that copy number alterations and LOH are rare and non-recurrent in Ollier ECs while secondary CS are genetically unstable. One could predict that instead small deletions, point mutations or epigenetic mechanisms play a role in the origin of ECs of Ollier disease.

关键词： expression array Copy Number Alteration Copy Number Gain Copy Number Alteration Tissue Micro array

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Altered gene expression in murine placentas in an infection-induced intrauterine growth restriction model: a microarray analysis

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JOURNAL OF REPRODUCTIVE IMMUNOLOGY 2010年第2期85卷 140-148页

作者： Bobetsis, Y. A. Barros, S. P. Lin, D. M. Arce, R. M. Offenbacher, S. Univ Athens Athens 11527 Greece Univ N Carolina Sch Dent N Carolina Oral Hlth Inst Durham NC 27709 USA Gen Dent Katy TX 77450 USA

The biological mechanisms leading to incomplete intrauterine growth are not completely elucidated and few studies have investigated infection-mediated growth restriction. In this investigation we report the alterations induced by maternal infectious challenge in placental gene expression patterns using a murine model. Pregnant dams were challenged at day E7.5 with the oral human pathogen Campylobacter rectus to elicit fetal growth restriction. At embryonic day E16.5 placentas were collected to compare placental gene expression patterns from normal fetuses of unchallenged dams and growth restricted fetuses from infected dams. Differential gene expression patterns were determined using Agilent Oligo array (G4121A) with a false discovery rate of P < 0.05 and pathway analyses were performed. Seventy-four genes were differentially expressed during infection-mediated growth restriction with 9 genes significantly up-regulated, indicating that the effects of maternal infection on gene expression were predominantly suppressive. Pathway analyses indicated that 46 of the 65 genes that were significantly down-regulated were associated with placental/fetal development, and 26 of those were imprinted genes. Among the 9 genes that were up-regulated, 4 are involved in oxygen supply to the fetus and the development of the vascular system. Microarray analysis demonstrated that in the pregnant mouse model, maternal infection that induced growth restriction was associated with down-regulated placental expression of critical growth and developmental related genes, including many imprinted genes. These findings may have significant implications for our understanding of the mechanisms underlying infection-associated human fetal growth restriction and the role of differential placental expression of imprinted genes in fetal growth. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

关键词： Fetal growth expression array Placenta Infection Development

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Positive and negative cis-regulatory elements directing postfertilization maternal mRNA translational control in mouse embryos

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AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY 2010年第4期299卷 C818-C827页

作者： Potireddy, Santhi Midic, Uros Liang, Cheng-Guang Obradovic, Zoran Latham, Keith E. Temple Univ Fels Inst Canc Res & Mol Biol Coll Sci & Technol Informat Sci & Technol Ctr Philadelphia PA 19122 USA Temple Univ Dept Biochem Coll Sci & Technol Informat Sci & Technol CtrSch Med Philadelphia PA 19122 USA Temple Univ Dept Comp & Informat Sci Coll Sci & Technol Informat Sci & Technol Ctr Philadelphia PA 19140 USA

Potireddy S, Midic U, Liang CG, Obradovic Z, Latham KE. Positive and negative cis-regulatory elements directing postfertilization maternal mRNA translational control in mouse embryos. Am J Physiol Cell Physiol 299: C818-C827, 2010. First published June 23, 2010;doi:10.1152/ajpcell.00166.2010.-Mechanisms providing for temporally complex patterns of maternal mRNA translation after fertilization are poorly understood. We employed bioinformatics analysis to compare populations of mRNAs enriched specifically on polysomes at the metaphase II (MII) stage oocyte and late one-cell stages and a detailed deletion/truncation series to identify elements that regulate translation. We used the Bag4 3' untranslated region (UTR) as a model. Bioinformatics analysis revealed one conserved motif, subsequently confirmed by functional studies to be a key translation repressor element. The deletion/truncation studies revealed additional regulatory motifs, most notably a strong translation activator element of <30 nt. Analysis of mRNA secondary structure suggests that secondary structure plays a key role in translation repression. Additional bioinformatics analysis of the regulated mRNA population revealed a diverse collection of regulatory motifs found in small numbers of mRNAs, highlighting a high degree of sequence diversity and combinatorial complexity in the overall control of the maternal mRNA population. We conclude that translational control after fertilization is driven primarily by negative regulatory mechanisms opposing strong translational activators, with stage-specific release of the inhibitory influences to permit recruitment. The combination of bioinformatics analysis and deletion/truncation studies provides the necessary approach for dissecting postfertilization translation regulatory mechanisms.

关键词： expression array oocyte polyribosome messenger RNA motif zygote

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Leukemia inhibitory factor receptor (LIFR) is detected as a novel suppressor gene of hepatocellular carcinoma using double-combination array

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CANCER LETTERS 2010年第2期289卷 170-177页

作者： Okamura, Yukiyasu Nomoto, Shuji Kanda, Mitsuro Li, Qiyong Nishikawa, Yoko Sugimoto, Hiroyuki Kanazumi, Naohito Takeda, Shin Nakao, Akimasa Nagoya Univ Dept Surg 2 Grad Sch & Med Showa Ku Nagoya Aichi 4668550 Japan

Hepatocellular carcinoma (HCC) is one of the world's top five causes of cancer-related deaths and treatment options are limited in this type of cancer. In the present study, we attempt to identify the novel suppressor genes of HCC using a double-combination array we designed. Leukemia inhibitory factor receptor (LIFR) is one of suppressor genes using this method. We found that 23 of 48 (47.9%) tumor tissues showed promoter hypermethylation of LIFR gene, and the expression level was clearly reduced in tumor tissues (P < 0.0001). The present study suggests that our method is a meaning technique able to detect novel genes and that LIFR gene is a new suppressor gene of HCC. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

关键词： Hepatocellular carcinoma Leukemia inhibitory factor receptor Tumor suppressor gene expression array Single nucleotide polymorphism array

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Gene expression array analyses predict increased proto-oncogene expression in MMTV induced mammary tumors

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VIRUS RESEARCH 2006年第2期119卷 177-186页

作者： Popken-Harris, Pamela Kirchhof, Nicole Harrison, Ben Harris, Lester F. Abbott NW Hosp David F Hickok Mem Canc Res Lab Minneapolis MN 55407 USA Univ Minnesota Ctr Canc Minneapolis MN 55455 USA Univ Minnesota Vet Diagnost Lab St Paul MN 55108 USA

Exogenous infection by milk-borne mouse mammary tumor viruses (MMTV) typically induce mouse mammary tumors in genetically susceptible mice at a rate of 90-95% by 1 year of age. In contrast to other transforming retroviruses, MMTV acts as an insertional mutagen and under the influence of steroid hormones induces oncogenic transformation after insertion into the host genome. As these events correspond with increases in adjacent *** transcription, we used expression array profiling to determine which commonly associated MMTV insertion site protooncogenes were transcriptionally active in MMTV induced mouse mammary tumors. To verify our gene expression array results we developed real-time quantitative RT-PCR assays for the common MMTV insertion site genes found in RIII/Sa mice (int-1/wnt-1, int-21fgf-3, int-3/Notch 4, and fg/8/AIGF) as well as two genes that were consistently up regulated (CCND1, and MAT-8) and two genes that were consistently down regulated (FN1 and MAT-8) in the MMTV induced tumors as compared to normal mammary gland. Finally, each tumor was also examined hi stopathologically. Our expression array findings support a model whereby just one or a few common MMTV insertions into the host genome sets up a dominant cascade of events that leave a characteristic molecular signature. (c) 2006 Elsevier B.V. All rights reserved.

关键词： MMTV expression array proto-oncogene RT-PCR

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IGF2 is Highly Expressed in Pediatric Undifferentiated Sarcomas and Reveals Two Distinct Cytoplasmic Trafficking Patterns

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PEDIATRIC AND DEVELOPMENTAL PATHOLOGY 2010年第3期13卷 169-177页

作者： Somers, Gino R. Ho, Michael Pienkowska, Malgorzata Shlien, Adam Malkin, David Ackerley, Cameron Zielenska, Maria Hosp Sick Children Dept Paediat Lab Med Toronto ON M5G 1X8 Canada Univ Toronto Dept Lab Med & Pathobiol Toronto ON Canada Hosp Sick Children Dept Genet & Genom Biol Toronto ON M5G 1X8 Canada Univ Toronto Dept Med Biophys Toronto ON Canada Hosp Sick Children Dept Pediat Toronto ON M5G 1X8 Canada

Pediatric undifferentiated soft tissue sarcomas (USTSs) are tumors composed of primitive mesenchymal cells. As such, they form an attractive model for studying the early events in sarcoma development. In an effort to better understand the critical molecular aberrations leading to sarcoma development, gene expression array analysis and post-array validation techniques were applied to several USTSs;the results were consistent with upregulation of the excitatory components of the insulin-like growth factor (IGF) pathway. Particularly high expression of the insulin-like growth factor 2 (IGF2) ligand was seen and confirmed by real-time reverse transcriptase-polymerase chain reaction. Immunohistochemistry performed using antibodies against IGF2 revealed overexpression of the IGF2 protein in 19 of 21(90%) USTSs and revealed 2 distinct staining patterns, 1 in which there was diffuse cytoplasmic staining (16/19) and 1 in which there was punctate perinuclear positivity (3/19). Using ultrastructural immunogold localization of IGF2, it was determined that IGF2 was primarily localized to Golgi-derived vesicles and multivesicular bodies in tumor cells showing the punctate pattern, and to both the cytoplasm and plasma membrane of tumor cells showing the diffuse pattern. The results suggest that upregulation of the IGF pathway in pediatric USTSs is a critical early event in the development of sarcomas. Furthermore, findings from the immunocytochemical and immunogold analyses confirm the presence of 2 different cytoplasmic trafficking patterns and storage motifs of IGF2 within this type of tumor. Given that in one subcellular pattern the IGF2 protein does not appear to reach the membrane, these findings may have functional significance.

关键词： expression array IGF2 immunogold immunohistochemistry pediatric undifferentiated sarcoma

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