Identification of target genes in laryngeal squamous cell carcinoma by high-resolution copy number and gene expression microarray analyses

Järvinen, Anna-Kaarina; Autio, Reija; Haapa-Paananen, Saija; Wolf, Maija; Saarela, Matti; Grénman, Reidar; Leivo, Ilmo; Kallioniemi, Olli; Mäkitie, Antti; Monni, Outi

doi:10.1038/sj.onc.1209690

Cited by 87 publications

(87 citation statements)

References 37 publications

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“…In agreement with our findings, very recently, Järvinen et al (32) proposed that FADD and PPFIA1 are likely candidates, implicating that these two genes are located near the core of the amplicon. However, our comprehensive analysis of all genes in the 11q13 region revealed that, in addition to FADD and PPFIA1, six other likely candidate genes (TPCN2, CCND1, FLJ42258, ORAOV1, FGF19, and CTTN) within the 11q13.3 CRA are coamplified in at least 25 of 29 cases and show a strong correlation between expression and amplification (Table 1).…”

Section: Discussionsupporting

confidence: 81%

Amplicon Mapping and Expression Profiling Identify the Fas-Associated Death Domain Gene as a New Driver in the 11q13.3 Amplicon in Laryngeal/Pharyngeal Cancer

Gibcus¹,

Menkema²,

Mastik³

et al. 2007

Clinical Cancer Research

109

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Purpose: Amplification of the 11q13 region is a frequent event in human cancer. The highest incidence (36%) is found in head and neck squamous cell carcinomas. Recently, we reported that the amplicon size in 30 laryngeal and pharyngeal carcinomas with 11q13 amplification is determined by unique genomic structures, resulting in the amplification of a set of genes rather than a single gene. Experimental Design: To investigate which gene(s) drive the 11q13 amplicon, we determined the smallest region of overlap with amplification and the expression levels of all genes within this amplicon. Results: Using array-based comparative genomic hybridization analysis, we detected a region of f1.7 Mb containing 13 amplified genes in more than 25 of the 29 carcinomas. Quantitative reverse transcription-PCR revealed that overexpression of 8 potential driver genes including, cyclin D1, cortactin, and Fas-associated death domain (FADD), correlated significantly with DNA amplification. FADD protein levels correlated well with DNA amplification, implicating that FADD is also a candidate driver gene in the 11q13 amplicon. Analysis of 167 laryngeal carcinomas showed that increased expression of FADD (P = 0.007) and Ser 194 phosphorylated FADD (P = 0.011) were associated with a worse disease-specific survival. FADD was recently reported to be involved in cell cycle regulation, and cancer cells expressing high levels of the Ser 194 phosphorylated isoform of FADD proved to be more sensitive to Taxol-induced cell cycle arrest. Conclusion: Because of the frequent amplification of the 11q13 region and concomitant overexpression of FADD in head and neck squamous cell carcinomas, we hypothesize that FADD is a marker to select patients that might benefit fromTaxol-based chemoradiotherapy.

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Section: Discussionsupporting

confidence: 81%

Amplicon Mapping and Expression Profiling Identify the Fas-Associated Death Domain Gene as a New Driver in the 11q13.3 Amplicon in Laryngeal/Pharyngeal Cancer

Gibcus¹,

Menkema²,

Mastik³

et al. 2007

Clinical Cancer Research

109

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“…We have recently shown that liprin-a1 is an essential regulator of cell spreading on extracellular matrix (ECM) (Asperti et al, 2009(Asperti et al, , 2010. Interestingly, the gene for liprin-a1 is included in the human chromosomal region 11q13 (Katoh and Katoh, 2005;Ja¨rvinen et al, 2006) that is frequently amplified in various malignant tumors, including B20% of breast cancers (Al-Kuraya et al, 2004). Based on this information, we have addressed the role of liprin-a1 in the regulation of the different cellular processes required for the invasion of the MDA-MB-231 breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Liprin-α1 regulates breast cancer cell invasion by affecting cell motility, invadopodia and extracellular matrix degradation

et al. 2010

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Migration of cells and degradation of the extracellular matrix (ECM) are required for efficient tumor cell invasion, but the underlying molecular mechanisms are only partially known. The PPFIA1 gene for liprin-a1 is frequently amplified in human breast cancers. We recently demonstrated that liprin-a1 is an important regulator of cell edge dynamics during motility. We show, herein, that the liprin-a1 protein is highly expressed in human breast tumors. Functional analysis shows that liprin-a1 is specifically required for the migration and invasion of highly invasive human breast cancer MDA-MB-231 cells. We used time-lapse analysis to demonstrate defects in the motility of liprin-a1-depleted cells that include a striking instability of the lamellipodia. Liprin-a1 levels altered by either RNA interference or overexpression affected also cell spreading and the number of invadopodia per cell, but not the density of invadopodia per unit of surface area. On the other hand, silencing of liprin-a1 inhibited the degradation of the ECM, whereas its overexpression enhanced degradation, resulting in significant negative or positive effects, respectively, on the area of degradation per invadopodium. Transfection of fluorescent-labeled cortactin revealed that depletion of liprin-a1 also affected the assembly and disassembly of invadopodia, with decrease of their lifetime. Our results strongly support a novel important role of liprin-a1 in the regulation of human tumor cell invasion.

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“…The cell lines were previously characterized. 4,5 Cells were grown in adhesive 25 cm 2 flasks in standard Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum at 37°C under 5% CO 2 atmosphere. Cells were harvested at a confluence of 70%-90%.…”

Section: Lscc Cell Lines Primary Tumors and The Control Samplesmentioning

confidence: 99%

Recurrent epigenetic silencing of the PTPRD tumor suppressor in laryngeal squamous cell carcinoma

et al. 2017

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Cellular processes like differentiation, mitotic cycle, and cell growth are regulated by tyrosine kinases with known oncogenic potential and tyrosine phosphatases that downmodulate the first. Therefore, tyrosine phosphatases are recurrent targets of gene alterations in human carcinomas. We and others suggested recently a tumor suppressor function of the PTPRD tyrosine phosphatase and reported homozygous deletions of the PTPRD locus in laryngeal squamous cell carcinoma. In this study, we investigated other gene-inactivating mechanisms potentially targeting PTPRD, including loss-of-function mutations and also epigenetic alterations like promoter DNA hypermethylation. We sequenced the PTPRD gene in eight laryngeal squamous cell carcinoma cell lines but did not identify any inactivating mutations. In contrast, by bisulfite pyrosequencing of the gene promoter region, we identified significantly higher levels of methylation (p = 0.001 and p = 0.0002, respectively) in 9/14 (64%) laryngeal squamous cell carcinoma cell lines and 37/79 (47%) of primary laryngeal squamous cell carcinoma tumors as compared to normal epithelium of the upper aerodigestive tract. There was also a strong correlation (p = 0.0001) between methylation and transcriptional silencing for the PTPRD gene observed in a cohort of 497 head and neck tumors from The Cancer Genome Atlas dataset suggesting that DNA methylation is the main mechanism of PTPRD silencing in these tumors. In summary, our data provide further evidence of the high incidence of PTPRD inactivation in laryngeal squamous cell carcinoma. We suggest that deletions and lossof-function mutations are responsible for PTPRD loss only in a fraction of cases, whereas DNA methylation is the dominating mechanism of PTPRD inactivation.

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Identification of target genes in laryngeal squamous cell carcinoma by high-resolution copy number and gene expression microarray analyses

Cited by 87 publications

References 37 publications

Amplicon Mapping and Expression Profiling Identify the Fas-Associated Death Domain Gene as a New Driver in the 11q13.3 Amplicon in Laryngeal/Pharyngeal Cancer

Amplicon Mapping and Expression Profiling Identify the Fas-Associated Death Domain Gene as a New Driver in the 11q13.3 Amplicon in Laryngeal/Pharyngeal Cancer

Liprin-α1 regulates breast cancer cell invasion by affecting cell motility, invadopodia and extracellular matrix degradation

Recurrent epigenetic silencing of the PTPRD tumor suppressor in laryngeal squamous cell carcinoma

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