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Identification of Genes Associated with Tumorigenesis of Meibomian Cell Carcinoma by Microarray Analysis ⁎ Arun Kumar A, , Syril Kumar Dorairaj B, Venkatesh C

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Identification of Genes Associated with Tumorigenesis of Meibomian Cell Carcinoma by Microarray Analysis ⁎ Arun Kumar A, , Syril Kumar Dorairaj B, Venkatesh C View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Available online at www.sciencedirect.com Genomics 90 (2007) 559–566 www.elsevier.com/locate/ygeno Identification of genes associated with tumorigenesis of meibomian cell carcinoma by microarray analysis ⁎ Arun Kumar a, , Syril Kumar Dorairaj b, Venkatesh C. Prabhakaran b, D. Ravi Prakash b, Sanjukta Chakraborty a a Department of Molecular Reproduction, Development, and Genetics, Indian Institute of Science, Bangalore 560012, India b Minto Ophthalmic Hospital, Bangalore, India Received 15 May 2007; accepted 20 July 2007 Available online 21 September 2007 Abstract Meibomian cell carcinoma (MCC) is a malignant tumor of the meibomian glands located in the eyelids. No information exists on the cytogenetic and genetic aspects of MCC. There is no report on the gene expression profile of MCC. Thus there is a need, for both scientific and clinical reasons, to identify genes and pathways that are involved in the development and progression of MCC. We analyzed the gene expression profile of MCC by the microarray technique. Forty-four genes were upregulated and 149 genes were downregulated in MCC. Differential expression data were confirmed for 5 genes by semiquantitative RT-PCR in MCC tumors: GTF2H4, RBM12, UBE2D3, DDX17, and LZTS1. We found dysregulation of two major pathways in MCC: MAPK and JAK/STAT. Clusters of genes on chromosomes 1, 12, and 19 were dysregulated in MCC. The data presented here will facilitate the identification of specific markers and therapeutic targets for the treatment of MCC patients. © 2007 Elsevier Inc. All rights reserved. Keywords: Expression profile; Meibomian cell carcinoma; MAPK signaling pathway; JAK/STAT pathway; Microarrays Meibomian glands are responsible for the maintenance of the Although microarray analysis has been used extensively to health and integrity of the ocular surface. They promote stability provide a vast amount of knowledge on cancer etiology and and prevent evaporation of the preocular tear film through the biomarkers for therapeutic applications by profiling the synthesis and secretion of lipids at the lid margin [1]. First transcriptome of many cancers, no microarray analysis has described by Meibomius, these oil-producing sebaceous glands been done previously on this tumor. The main aim of this study number around 30–40 in the upper and 20–30 in the lower was to identify genes involved in the tumorigenesis of this eyelids [2]. Meibomian cell carcinoma (MCC), also referred to tumor. We report the first gene expression profile of this tumor as sebaceous carcinoma, is a malignant tumor that occurs most using cDNA microarray analysis. commonly on the eyelids [3]. Although rare, MCC is the fourth most common tumor among eyelid tumors after basal cell Results carcinoma, squamous cell carcinoma, and cutaneous melanomas [4]. Local recurrence and regional lymph node metastasis are Differential gene expression in MCC common in MCC. In addition, this neoplasm has also been reported to spread to the trigeminal ganglion and cerebellum [5]. Microarray analysis of MCC yielded a data set with 193 The only known therapy for this cancer is the surgical excision of differentially regulated genes. Of these, 44 genes were the tumor, but it reappears after some time following the surgery. upregulated and 149 were downregulated (Supplemental Table Nothing is known about the cytogenetic and genetic events 1S). These included genes involved in various cellular functions involved in the development and progression of this neoplasm. such as cell cycle and cell proliferation, signal transduction, transcription and translation, cell death and apoptosis, enzyme ⁎ Corresponding author. Fax: +91 80 2360 0999. metabolism, and cell adhesion. Some of the selected genes are E-mail address: [email protected] (A. Kumar). listed in Table 1. Our analysis showed dysregulation of two 0888-7543/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ygeno.2007.07.008 560 A. Kumar et al. / Genomics 90 (2007) 559–566 Table 1 Selected differentially regulated genes with known function in MCC Gene Symbol UniGene Chromosome Expt 1 Expt 2 Average location ratio Cell cycle/cell proliferation DEAD (Asp-Glu-Ala-Asp) box polypeptide 17 DDX17 Hs.528305 22q13.1 0.278 0.201 0.240 Leucine zipper, putative tumor suppressor 1 LZTS1 Hs.521432 8p22 0.453 0.463 0.458 CDK2-associated protein 1 CDK2AP1 Hs.433201 12q24.31 0.374 0.598 0.486 Metallothionein 3 (growth inhibitory factor) MT3 Hs.73133 16q13 0.449 0.532 0.491 Glycoprotein (transmembrane) nmb GPNMB Hs.190495 7p15 0.400 0.583 0.492 DEAD (Asp-Glu-Ala-As) box polypeptide 19 DDX19B Hs.221761 16q22.1 2.197 4.079 3.138 Signal transduction/kinases Signal transducer and activator of transcription 2 STAT2 Hs.530595 12q13.2 0.301 0.543 0.422 Casein kinase 1, ε CSNK1E Hs.474833 22q13.1 0.273 0.606 0.440 Serum/glucocorticoid-regulated kinase SGK Hs.510078 6q23 0.393 0.567 0.480 Tyrosine 3-mono-oxygenase β polypeptide YWHAB Hs.651212 20q13.1 0.470 0.513 0.492 Neuronal PAS domain protein 3 NPAS3 Hs.659456 14q12–q13 0.418 0.590 0.504 Centaurin, β1 CENTB1 Hs.337242 17p13.1 0.578 0.431 0.505 Amyloid β (A4) precursor protein-binding, APBB2 Hs.479602 4p14 0.424 0.590 0.507 family B, member 2 Dual-specificity phosphatase 19 DUSP19 Hs.132237 2q32.1 0.402 0.614 0.508 Serine/threonine kinase 38 STK38 Hs.409578 6p21 0.568 0.451 0.510 Phospholipase C, δ4 PLCD4 Hs.632528 2q35 0.539 0.494 0.517 MAP/microtubule affinity-regulating kinase 4 MARK4 Hs.34314 19q13.32 2.577 1.773 2.180 Interleukin 23, α subunit p19 IL23A Hs.98309 12q13.2 1.664 5.726 3.700 Transcription/translation NSFL1 (p97) cofactor (p47) NSFL1C Hs.12865 20p13 0.304 0.326 0.315 Ribosomal protein S4, X-linked RPS4X Hs.446628 Xq13.1 0.280 0.599 0.440 Nuclear factor of activated T cells 5 NFAT5 Hs.371987 16q22.1 0.516 0.451 0.483 General transcription factor IIH, polypeptide 1 GTF2H1 Hs.577202 11p15.1–p14 0.585 0.461 0.523 Homeobox C9 HOXC9 Hs.658823 12q13.13 0.607 0.470 0.539 BarH-like homeobox 1 BARX1 Hs.164960 9q12 2.335 1.997 2.166 Activating signal cointegrator 1 complex subunit 2 ASCC2 Hs.517438 22q12.1 1.678 2.874 2.276 Polymerase (RNA) II (DNA-directed) POLR2E Hs.24301 19p13.3 2.022 3.212 2.617 polypeptide E General transcription factor IIH, polypeptide 4 GTF2H4 Hs.485070 6p21.3 2.549 3.901 3.225 U5 snRNP-specific protein, 116 kDa EFTUD2 Hs.151787 17q21.31 1.789 4.869 3.329 RNA binding motif protein 12 RBM12 Hs.246413 20q11.21 2.701 4.378 3.540 Cell death/apoptosis Baculoviral IAP repeat-containing 4 BIRC4 Hs.356076 Xq25 0.245 0.507 0.376 Interleukin 24 IL24 Hs.658964 1q32.1 0.289 0.590 0.440 Growth arrest and DNA-damage-inducible, γ GADD45G Hs.9701 9q22 0.437 0.607 0.522 Tumor necrosis factor receptor superfamily, TNFRSF21 Hs.443577 6p21.1–p12.2 0.584 0.469 0.527 member 21 CD74 antigen CD74 Hs.694723 5q32 2.470 2.227 2.349 Enzyme/metabolism Ectonucleoside triphosphate diphosphohydrolase 2 ENTPD2 Hs.123036 9q34 0.301 0.210 0.256 Carbonic anhydrase XII CA12 Hs.210995 15q22 0.242 0.419 0.331 Betaine-homocysteine methyltransferase 2 BHMT2 Hs.114172 5q13 0.293 0.442 0.368 N-myristoyltransferase 2 NMT2 Hs.60339 10p13 0.206 0.596 0.401 Carboxypeptidase Z CPZ Hs.78068 4p16.1 0.385 0.489 0.437 Collectin subfamily member 12 COLEC12 Hs.464422 18pter–p11.3 0.302 0.609 0.456 Endo-β-N-acetylglucosaminidase FLJ21865 Hs.29288 17q25.3 0.490 0.456 0.473 Methylenetetrahydrofolate dehydrogenase MTHFD1 Hs.652308 14q24 0.373 0.597 0.485 Histidyl-tRNA synthetase 2 HARS2 Hs.432560 20p11.23 0.528 0.444 0.486 Scavenger receptor class A, member 3 SCARA3 Hs.128856 8p21 0.419 0.565 0.492 Pyruvate dehydrogenase kinase, isoenzyme 3 PDK3 Hs.658190 Xp22.11 1.757 2.907 2.332 Ubiquitin-conjugating enzyme E2D 3 UBE2D3 Hs.518773 4q24 2.139 3.282 2.711 Cell adhesion Keratin 1 (epidermolytic hyperkeratosis) KRT1 Hs.80828 12q13.13 0.195 0.612 0.404 Periplakin PPL Hs.192233 16p13.3 0.463 0.348 0.406 A. Kumar et al. / Genomics 90 (2007) 559–566 561 Table 1 (continued) Gene Symbol UniGene Chromosome Expt 1 Expt 2 Average location ratio Cell adhesion ARP3 actin-related protein 3 homolog (yeast) ACTR3 Hs.433512 2q14.1 0.470 0.426 0.448 Matrilin 1, cartilage matrix protein MATN1 Hs.150366 1p35.2 0.575 0.396 0.486 Sarcoglycan, ε SGCE Hs.371199 7q21–q22 0.613 0.378 0.496 Tubulointerstitial nephritis antigen TINAG Hs.127011 6p11.2–p12 2.129 1.995 2.062 Beaded filament structural protein 2, phakinin BFSP2 Hs.659862 3q21–q25 2.715 1.839 2.277 Thrombospondin 3 THBS3 Hs.169875 1q22 1.645 3.365 2.505 major pathways in MCC: mitogen-activated protein kinase DDX17, and LZTS1) in a panel of four MCC and two normal (MAPK) and Janus kinase/signal transducers and activators of eyelid tissues by semiquantitative RT-PCR analysis (Fig. 1). transcription (JAK/STAT) (Table 2). Nothing is known about the functional relevance of the To confirm the microarray results, we performed semiquan- GTF2H4 gene.
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