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1.
PLoS One ; 7(9): e45534, 2012.
Article in English | MEDLINE | ID: mdl-23029077

ABSTRACT

PURPOSE: Although promoter hypermethylation has been an accepted means of tumor suppressor gene inactivation, activation of otherwise normally repressed proto-oncogenes by promoter demethylation has been infrequently documented. EXPERIMENTAL DESIGN: In this study we performed an integrative, whole-genome analysis for discovery of epigenetically activated proto-oncogenes in head and neck cancer tumors. We used the 47K GeneChip U133 Plus 2.0 Affymetrix expression microarray platform to obtain re-expression data from 5-aza treated normal cell line and expression data from primary head and neck squamous cell carcinoma (HNSCC) tumor tissues and normal mucosa tissues. We then investigated candidate genes by screening promoter regions for CpG islands and bisulfite sequencing followed by QUMSP and RT PCR for the best candidate genes. Finally, functional studies were performed on the top candidate gene. RESULTS: From the top 178 screened candidates 96 had CpG islands in their promoter region. Seven candidate genes showed promoter region methylation in normal mucosa samples and promoter demethylation in a small cohort of primary HNSCC tissues. We then studied the demethylation of the top 3 candidate genes in an expanded cohort of 76 HNSCC tissue samples and 17 normal mucosa samples. We identified MAGEB2 as having significant promoter demethylation in primary head and neck squamous cell carcinoma tissues. We then found significantly higher expression of MAGEB2 in tumors in a separate cohort of 73 primary HNSCC tissues and 31 normal tissues. Finally, we found that MAGEB2 has growth promoting effects on minimally transformed oral keratinocyte cell lines but not a definite effect on HNSCC cell lines. CONCLUSION: In conclusion, we identified MAGEB2 as activated by promoter demethylation in HNSCCand demonstrates growth promoting effects in a minimally transformed oral keratinocyte cell line. More studies are needed to evaluate MAGBE2's exact role in HNSCC.


Subject(s)
Antigens, Neoplasm/genetics , Carcinoma, Squamous Cell/genetics , DNA Methylation , Head and Neck Neoplasms/genetics , Neoplasm Proteins/genetics , Promoter Regions, Genetic , Transcriptional Activation , Antimetabolites, Antineoplastic/pharmacology , Azacitidine/pharmacology , Cell Line, Tumor , Cell Proliferation , Epigenesis, Genetic , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Humans , Reproducibility of Results
2.
Oncol Rep ; 28(4): 1498-502, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22842486

ABSTRACT

Cancer testis antigens (CTAs) are proteins that are normally expressed only in male germ cells and are aberrantly upregulated in a variety of cancers such as melanomas and lung cancer. MAGEA proteins belong to Class I CTAs and are being utilized as targets for cancer immunotherapy. Despite the discovery of the first CTA (MAGEA1) 20 years ago, the functions of these proteins remain poorly understood and evidence suggests both oncogenic as well as tumor suppressive roles for these proteins. Herein, we investigated the role of MAGEA4 in promoting cell growth. When overexpressed, MAGEA4 promotes growth of spontaneously transformed normal oral keratinocytes (NOK-SI). To understand the mechanism of growth stimulation by MAGEA4, we explored the effect of overexpressing MAGEA4 on cell cycle and apoptosis. MAGEA4 inhibits growth arrest of cells in the G1 phase of the cell cycle. We also found that overexpression of MAGEA4 inhibits G418-induced apoptosis of NOK-SI cells. Interestingly, this inhibition was accompanied by repression of two p53 downstream genes, BAX and CDKN1A. Our results indicate that MAGEA4 promotes growth by preventing cell cycle arrest and by inhibiting apoptosis mediated by the p53 transcriptional targets.


Subject(s)
Antigens, Neoplasm/genetics , Apoptosis/genetics , Keratinocytes/cytology , Neoplasm Proteins/genetics , Antigens, Neoplasm/metabolism , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Cell Cycle Checkpoints/genetics , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p21/genetics , Gene Expression Regulation , Genes, p53 , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/pathology , Humans , Keratinocytes/physiology , Mouth/cytology , Neoplasm Proteins/metabolism , Squamous Cell Carcinoma of Head and Neck , bcl-2-Associated X Protein/genetics
3.
PLoS One ; 7(7): e40389, 2012.
Article in English | MEDLINE | ID: mdl-22792300

ABSTRACT

Testis-specific transcription factor BORIS (Brother of the Regulator of Imprinted Sites), a paralog and proposed functional antagonist of the widely expressed CTCF, is abnormally expressed in multiple tumor types and has been implicated in the epigenetic activation of cancer-testis antigens (CTAs). We have reported previously that suprabasin (SBSN), whose expression is restricted to the epidermis, is epigenetically derepressed in lung cancer. In this work, we establish that SBSN is a novel non-CTA target of BORIS epigenetic regulation. With the use of a doxycycline-inducible BORIS expressing vector, we demonstrate that relative BORIS dosage is critical for SBSN activation. At lower concentrations, BORIS induces demethylation of the SBSN CpG island and disruption and activation of chromatin around the SBSN transcription start site (TSS), resulting in a 35-fold increase in SBSN expression in the H358 human lung cancer cell line. Interestingly, increasing BORIS concentrations leads to a subsequent reduction in SBSN expression via chromatin repression. In a similar manner, increase in BORIS concentrations leads to eventual decrease of cell growth and colony formation. This is the first report demonstrating that different amount of BORIS defines its varied effects on the expression of a target gene via chromatin structure reorganization.


Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , DNA-Binding Proteins/physiology , Gene Expression Regulation, Neoplastic , Lung Neoplasms/metabolism , Neoplasm Proteins/genetics , Oncogenes , Antigens, Differentiation , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Cell Proliferation , Chromatin/metabolism , Chromatin Assembly and Disassembly , CpG Islands , DNA Methylation , Epigenesis, Genetic , Histones/metabolism , Humans , Lung Neoplasms/genetics , Neoplasm Proteins/metabolism , Transcription, Genetic
5.
Clin Cancer Res ; 17(13): 4267-76, 2011 Jul 01.
Article in English | MEDLINE | ID: mdl-21558405

ABSTRACT

PURPOSE: Aim of this study was to determine whether BORIS (Brother of the Regulator of Imprinted Sites) is a regulator of MAGEA2, MAGEA3, and MAGEA4 genes in lung cancer. EXPERIMENTAL DESIGN: Changes in expression of MAGEA genes upon BORIS induction/knockdown were studied. Recruitment of BORIS and changes in histone modifications at their promoters upon BORIS induction were analyzed. Luciferase assays were used to study their activation by BORIS. Changes in methylation at these promoters upon BORIS induction were evaluated. RESULTS: Alteration of BORIS expression by induction/knockdown directly correlated with expression of MAGEA genes. BORIS was enriched at their promoters in H1299 cells, which show high expression of these cancer testis antigens (CTA), compared with normal human bronchial epithelial (NHBE) cells which show low expression of the target CTAs. BORIS induction in A549 cells resulted in increased amounts of BORIS and activating histone modifications at their promoters along with a corresponding increase in their expression. Similarly, BORIS binding at these promoters in H1299 correlates with enrichment of activating modifications, whereas absence of BORIS binding in NHBE is associated with enrichment of repressive marks. BORIS induction of MAGEA3 was associated with promoter demethylation, but no methylation changes were noted with activation of MAGEA2 and MAGEA4. CONCLUSIONS: These data suggest that BORIS positively regulates these CTAs by binding and inducing a shift to a more open chromatin conformation with promoter demethylation for MAGEA3 or independent of promoter demethylation in case of MAGEA2 and MAGEA4 and may be a key effector involved in their derepression in lung cancer.


Subject(s)
Antigens, Neoplasm/genetics , Antigens, Neoplasm/metabolism , DNA-Binding Proteins/metabolism , Gene Expression Regulation, Neoplastic , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Promoter Regions, Genetic/genetics , Base Sequence , Cell Line , Cell Line, Tumor , DNA Methylation/genetics , DNA-Binding Proteins/genetics , Histones/metabolism , Humans , Male , Protein Binding
6.
Clin Cancer Res ; 17(13): 4320-30, 2011 Jul 01.
Article in English | MEDLINE | ID: mdl-21551254

ABSTRACT

PURPOSE: Salivary gland adenoid cystic carcinoma (ACC) is a rare malignancy that is poorly understood. To look for relevant oncogene candidates under the control of promoter methylation, an integrated, genome-wide screen was conducted. EXPERIMENTAL DESIGN: Global demethylation of normal salivary gland cell strains using 5-aza-2'-deoxycytidine (5-aza-dC) and trichostatin A (TSA), followed by expression array analysis was conducted. ACC-specific expression profiling was generated using expression microarray analysis of primary ACC and normal samples. Next, the two profiles were integrated to identify a subset of genes for further validation of promoter demethylation in ACC versus normal. Finally, promising candidates were further validated for mRNA, protein, and promoter methylation levels in larger ACC cohorts. Functional validation was then conducted in cancer cell lines. RESULTS: We found 159 genes that were significantly re-expressed after 5-aza-dC/TSA treatment and overexpressed in ACC. After initial validation, eight candidates showed hypomethylation in ACC: AQP1, CECR1, C1QR1, CTAG2, P53AIP1, TDRD12, BEX1, and DYNLT3. Aquaporin 1 (AQP1) showed the most significant hypomethylation and was further validated. AQP1 hypomethylation in ACC was confirmed with two independent cohorts. Of note, there was significant overexpression of AQP1 in both mRNA and protein in the paraffin-embedded ACC cohort. Furthermore, AQP1 was upregulated in 5-aza-dC/TSA-treated SACC83. Finally, AQP1 promoted cell proliferation and colony formation in SACC83. CONCLUSIONS: Our integrated, genome-wide screening method proved to be an effective strategy for detecting novel oncogenes in ACC. AQP1 is a promising oncogene candidate for ACC and is transcriptionally regulated by promoter hypomethylation.


Subject(s)
Carcinoma, Adenoid Cystic/genetics , DNA Methylation/genetics , Genetic Testing , Genome-Wide Association Study , Oncogenes/genetics , Salivary Gland Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/pharmacology , Aquaporin 1/genetics , Aquaporin 1/metabolism , Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Carcinoma, Adenoid Cystic/mortality , Carcinoma, Adenoid Cystic/pathology , Cell Line , Cell Line, Tumor , Cell Proliferation , Cytidine Triphosphate/analogs & derivatives , Cytidine Triphosphate/pharmacology , Epigenomics , Female , Gene Expression/drug effects , Gene Expression/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Middle Aged , Salivary Gland Neoplasms/mortality , Salivary Gland Neoplasms/pathology , Up-Regulation/drug effects
7.
Arch Otolaryngol Head Neck Surg ; 137(3): 286-93, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21422315

ABSTRACT

OBJECTIVE: To examine the role of MAGEA2 in the tumorigenesis of head and neck squamous cell carcinoma (HNSCC). DESIGN: Primary tissue microarray data and quantitative reverse transcription-polymerase chain reaction (RT-PCR) showed that MAGEA2 is differentially overexpressed in HNSCC. Functional analyses were then performed using MAGEA2 transfections and small-interfering RNA knockdowns with subsequent anchorage-dependent growth studies and cell cycle analyses. Quantitative RT-PCR was used to evaluate expression changes in p53 downstream targets after transfection of MAGEA2 into normal upper aerodigestive cell lines. RESULTS: MAGEA2 is differentially overexpressed in HNSCC. In addition, MAGEA2 promotes growth in normal oral keratinocytes, whereas knockdown of MAGEA2 in HNSCC cells decreases growth. Using the HCT116 p53 wt and null cell line system, transfection of MAGEA2 induced growth in the p53 wt cell line while providing no growth advantage in the p53 mutant cells. Subsequently, transfection of MAGEA2 induced a decrease in messenger RNA expression of the p53 downstream targets CDKN1A and BAX and decreased G1 arrest in cells allowed to remain confluent for longer than 48 hours. CONCLUSIONS: These data suggest that MAGEA2 is differentially expressed in HNSCC and functions, in part, through the p53 pathway by increasing cellular proliferation and abrogating cell cycle arrest. This improved understanding of MAGEA2 function and expression patterns will potentially allow for the improved ability to use MAGEA2 for detection, surveillance, and targeted therapeutics.


Subject(s)
Antigens, Neoplasm/genetics , Carcinoma, Squamous Cell/genetics , Otorhinolaryngologic Neoplasms/genetics , Animals , Carcinoma, Squamous Cell/pathology , Cell Cycle/genetics , Cell Division/genetics , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Fibroblasts/pathology , Gene Expression Regulation, Neoplastic/genetics , Gene Knockdown Techniques , Humans , Keratinocytes/pathology , Mice , Neoplasm Staging , Oligonucleotide Array Sequence Analysis , Otorhinolaryngologic Neoplasms/pathology , RNA, Messenger/genetics , RNA, Small Interfering/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transfection , Tumor Suppressor Protein p53/genetics
8.
Clin Cancer Res ; 16(3): 857-66, 2010 Feb 01.
Article in English | MEDLINE | ID: mdl-20103683

ABSTRACT

PURPOSE: This study aims to investigate the role of the aberrant expression of Transkelolase-like 1 (TKTL1) in head and neck squamous cell carcinoma (HNSCC) tumorigenesis and to characterize TKTL1 contribution to HNSCC tumorigenesis through aerobic glycolysis and HIF1alpha stabilization. EXPERIMENTAL DESIGN: TKTL1 promoter hypomethylation and mRNA/protein aberrant expression were studied in human HNSCC tumor samples and normal mucosas. Oncogenic functions of TKTL1 were examined in HNSCC cell line panels and tumor xenograft models with TKTL1 expression construct. The metabolite levels of fructose-6-phosphate, glyceraldehydes-3-phosphate, pyruvate, lactate, and the levels of HIF1alpha protein and its downsteam glycolytic targets were compared between the TKTL1-expressing and vehicle-expressing HNSCC cells. Meanwhile, the effects of HIF1alpha/glycolytic inhibitors were evaluated on the TKTL1 transfectants. RESULTS: TKTL1 exhibits high frequency of promoter hypomethylation in HNSCC tumors compared with the normal mucosas, correlating with its overexpression in HNSCC. Overexpression of TKTL1 in HNSCC cells promoted cellular proliferation and enhanced tumor growth in vitro and in vivo. Overexpression of TKTL1 increased the production of fructose-6-phosphate and glyceraldehyde-3-phosphate, in turn elevating the production of pyruvate and lactate, resulting in the normoxic stabilization of the malignancy-promoting transcription factor HIF1alpha and the upregulation of downstream glycolytic enzymes. Notably, the reduction of TKTL1 expression decreased HIF1alpha accumulation and inhibition with HIF1alpha and/or the glycolysis inhibitor could abrogate the growth effects mediated by TKTL1 overexpression. CONCLUSION: TKTL1 is a novel candidate oncogene that is epigenetically activated by aberrant hypomethlation and contributes to a malignant phenotype through altered glycolytic metabolism and HIF1alpha accumulation.


Subject(s)
Carcinoma, Squamous Cell/metabolism , Glycolysis , Head and Neck Neoplasms/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Promoter Regions, Genetic/genetics , Transketolase/genetics , Aerobiosis , Animals , Carcinoma, Squamous Cell/pathology , DNA Methylation , Head and Neck Neoplasms/pathology , Humans , Mice , Mice, Inbred NOD , Transketolase/metabolism , Up-Regulation
9.
PLoS One ; 4(12): e8189, 2009 Dec 04.
Article in English | MEDLINE | ID: mdl-19997593

ABSTRACT

BACKGROUND: Cancer/testis antigens (CTAs) were first discovered as immunogenic targets normally expressed in germline cells, but differentially expressed in a variety of human cancers. In this study, we used an integrative epigenetic screening approach to identify coordinately expressed genes in human non-small cell lung cancer (NSCLC) whose transcription is driven by promoter demethylation. METHODOLOGY/PRINCIPAL FINDINGS: Our screening approach found 290 significant genes from the over 47,000 transcripts incorporated in the Affymetrix Human Genome U133 Plus 2.0 expression array. Of the top 55 candidates, 10 showed both differential overexpression and promoter region hypomethylation in NSCLC. Surprisingly, 6 of the 10 genes discovered by this approach were CTAs. Using a separate cohort of primary tumor and normal tissue, we validated NSCLC promoter hypomethylation and increased expression by quantitative RT-PCR for all 10 genes. We noted significant, coordinated coexpression of multiple target genes, as well as coordinated promoter demethylation, in a large set of individual tumors that was associated with the SCC subtype of NSCLC. In addition, we identified 2 novel target genes that exhibited growth-promoting effects in multiple cell lines. CONCLUSIONS/SIGNIFICANCE: Coordinated promoter demethylation in NSCLC is associated with aberrant expression of CTAs and potential, novel candidate protooncogenes that can be identified using integrative discovery techniques. These findings have significant implications for discovery of novel CTAs and CT antigen directed immunotherapy.


Subject(s)
Antigens, Neoplasm/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , Genetic Testing/methods , Lung Neoplasms/genetics , Cell Line, Tumor , Cell Proliferation , DNA Methylation/genetics , Genes, Neoplasm/genetics , Humans , Promoter Regions, Genetic/genetics
10.
PLoS One ; 4(3): e4961, 2009.
Article in English | MEDLINE | ID: mdl-19305507

ABSTRACT

BACKGROUND: Epigenetic alterations have been implicated in the pathogenesis of solid tumors, however, proto-oncogenes activated by promoter demethylation have been sporadically reported. We used an integrative method to analyze expression in primary head and neck squamous cell carcinoma (HNSCC) and pharmacologically demethylated cell lines to identify aberrantly demethylated and expressed candidate proto-oncogenes and cancer testes antigens in HNSCC. METHODOLOGY/PRINCIPAL FINDINGS: We noted coordinated promoter demethylation and simultaneous transcriptional upregulation of proto-oncogene candidates with promoter homology, and phylogenetic footprinting of these promoters demonstrated potential recognition sites for the transcription factor BORIS. Aberrant BORIS expression correlated with upregulation of candidate proto-oncogenes in multiple human malignancies including primary non-small cell lung cancers and HNSCC, induced coordinated proto-oncogene specific promoter demethylation and expression in non-tumorigenic cells, and transformed NIH3T3 cells. CONCLUSIONS/SIGNIFICANCE: Coordinated, epigenetic unmasking of multiple genes with growth promoting activity occurs in aerodigestive cancers, and BORIS is implicated in the coordinated promoter demethylation and reactivation of epigenetically silenced genes in human cancers.


Subject(s)
Antigens, Neoplasm , Epigenesis, Genetic , Head and Neck Neoplasms/genetics , Lung Neoplasms/genetics , Promoter Regions, Genetic , Proto-Oncogenes , Animals , Antigens, Neoplasm/genetics , Antigens, Neoplasm/metabolism , Base Sequence , Cell Line, Tumor , DNA Methylation , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Head and Neck Neoplasms/metabolism , Humans , Lung Neoplasms/metabolism , Microarray Analysis , Molecular Sequence Data , Proto-Oncogene Mas , Transketolase/genetics , Transketolase/metabolism
11.
Oral Oncol ; 45(4-5): 440-6, 2009.
Article in English | MEDLINE | ID: mdl-18674958

ABSTRACT

During the past decade, there has been a significant increase in knowledge regarding the molecular biology and epigenetics of head and neck squamous cell carcinoma (HNSCC). This has been aided by the steady development of new technology and novel techniques aimed at elucidating additional aberrant molecular alterations characteristic of HNSCC, including the advent of high throughput assays and the development of more sophisticated bioinformatics tools. In addition, advancements in the field of cancer epigenetics and microRNA have increased the complexity of understanding HNSCC tumorigenesis. These advances have lead to an increasing number of translational studies in the diagnosis, prognosis, and treatment of head and neck cancer. The end result is that molecular biomarkers, gene detection panels and targeted therapeutics are becoming a reality for the care of patients with HNSCC. In this article, we will focus on the many implications of this research as it pertains to clinical practice and the treatment of HNSCC patients.


Subject(s)
Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/therapy , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/therapy , Computational Biology/methods , DNA Methylation , Epigenesis, Genetic , ErbB Receptors , Gene Silencing , Genes, Tumor Suppressor , Human papillomavirus 16/pathogenicity , Human papillomavirus 18/pathogenicity , Humans , Loss of Heterozygosity , Molecular Biology/methods , Research
12.
Oral Oncol ; 45(4-5): 335-9, 2009.
Article in English | MEDLINE | ID: mdl-18674960

ABSTRACT

It is well known that cellular DNA alterations can lead to the formation of cancer, and there has been much discovery in the pathways involved in the development of head and neck squamous cell carcinoma (HNSCC). With novel genome-wide molecular assays, our ability to detect these abnormalities has increased. We now have a better understanding of the molecular complexity of HNSCC, but there is still much research to be done. In this review, we discuss the well described genetic alterations and touch on the newer findings, as well as some of the future directions of head and neck cancer research.


Subject(s)
Carcinoma, Squamous Cell/genetics , Head and Neck Neoplasms/genetics , Cytogenetic Analysis , Gene Expression Profiling/methods , Genes, Tumor Suppressor , Humans , Loss of Heterozygosity , Mitochondria/genetics , Molecular Biology/methods , Oligonucleotide Array Sequence Analysis/methods , Oncogenes/genetics , Research
14.
Oral Oncol ; 42(2): 201-7, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16266817

ABSTRACT

Constituents of tobacco can cause DNA adduct formation and are implicated in head and neck squamous cell cancer (HNSC) development. We investigated the capacity of HNSC cell lines to repair mitochondrial DNA (mtDNA) damage induced by a DNA adduct-forming agent. HNSC cell lines underwent 4-nitroquinoline 1-oxide (4NQO) exposure with subsequent rescue with normal media. Real-time quantitative PCR for nuclear DNA (nDNA) and mtDNA was performed. mtDNA to nDNA ratios were calculated and standardized to mock-treated cells to assess mtDNA repair ability. Two of three tested cancer cell lines exposed to 4NQO exhibited consistent decreases in mtDNA/nDNA ratios throughout the different repair timepoints. At 24 h mtDNA/nDNA ratios of JHU-O19 and JHU-O22 decreased to 63% and 60% of controls, respectively. Conversely, a control keratinocyte cell line exhibited overall increases in mtDNA/nDNA ratios compared to baseline suggesting intact DNA repair mechanisms. By using a DNA adduct formation and repair model featuring 4NQO and HNSC cell lines, we have implicated faulty mtDNA repair as having a potential role in HNSC.


Subject(s)
Carcinoma, Squamous Cell/genetics , DNA Repair , DNA, Mitochondrial/drug effects , DNA, Neoplasm/drug effects , Head and Neck Neoplasms/genetics , Quinolones/toxicity , 4-Nitroquinoline-1-oxide/toxicity , Carcinoma, Squamous Cell/pathology , DNA Adducts/biosynthesis , DNA Adducts/drug effects , DNA Damage , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , DNA, Neoplasm/genetics , DNA, Neoplasm/metabolism , Head and Neck Neoplasms/pathology , Humans , Oxidative Stress , Polymerase Chain Reaction/methods , Tumor Cells, Cultured
15.
Cancer Res ; 62(12): 3335-9, 2002 Jun 15.
Article in English | MEDLINE | ID: mdl-12067969

ABSTRACT

The gene most commonly altered in human glioblastomas is the epidermalgrowth factor receptor (EGFR). We profiled transcripts induced by mutantEGFR to better understand its role in tumor progression. The pattern found suggested enhanced tumor invasion. The highly induced genes included extracellular matrix components, metalloproteases, and a serine protease. We confirmed that mutant EGFR did make glioblastoma cells both more motile and invasive using in vitro assays. Furthermore, inhibitors of EGFR (OSI-774 and Tyrphostin AG1478) selectively down-regulated these molecular effectors in glioblastoma cells, eliminating enhanced invasion.


Subject(s)
ErbB Receptors/physiology , Extracellular Matrix Proteins/genetics , Glioblastoma/genetics , Animals , Enzyme Inhibitors/pharmacology , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/biosynthesis , ErbB Receptors/genetics , Extracellular Matrix Proteins/biosynthesis , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Metalloendopeptidases/biosynthesis , Metalloendopeptidases/genetics , Mice , Mice, Nude , Neoplasm Invasiveness , Quinazolines , Reverse Transcriptase Polymerase Chain Reaction , Serine Endopeptidases/biosynthesis , Serine Endopeptidases/genetics , Transfection , Tumor Cells, Cultured , Tyrphostins/pharmacology , Up-Regulation
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