Down-regulation of stem cell genes, including those in a 200-kb gene cluster at 12p13.31, is associated with in vivo differentiation of human male germ cell tumors Journal Article

  

Authors:	Korkola, J. E.; Houldsworth, J.; Chadalavada, R. S. V.; Olshen, A. B.; Dobrzynski, D.; Reuter, V. E.; Bosl, G. J.; Chaganti, R. S. K.
Article Title:	Down-regulation of stem cell genes, including those in a 200-kb gene cluster at 12p13.31, is associated with in vivo differentiation of human male germ cell tumors
Abstract:	Adult male germ cell tumors (GCTs) comprise distinct groups: seminomas and nonseminomas, which include pluripotent embryonal carcinomas as well as other histologic subtypes exhibiting various stages of differentiation. Almost all GCTs show 12p gain, but the target genes have not been clearly defined. To identify 12p target genes, we examined Affymetrix (Santa Clara, CA) U133A+B microarray (∼ 83% coverage of 12p genes) expression profiles of 17 seminomas, 84 nonseminoma GCTs, and 5 normal testis samples. Seventy-three genes on 12p were significantly overexpressed, including GLUT3 and REA (overexpressed in all GCTs) and CCND2 and FLJ22028 (overexpressed in all GCTs, except choriocarcinomas). We characterized a 200-kb gene cluster at 12p13.31 that exhibited coordinated overexpression in embryonal carcinomas and seminomas, which included the known stem cell genes NANOG, STELLA, and GDF3 and two previously uncharacterized genes. A search for other coordinately regulated genomic clusters of stem cell genes did not reveal any genomic regions similar to that at 12p13.31. Comparison of embryonal carcinoma with seminomas revealed relative overexpression of several stem cell-associated genes in embryonal carcinoma, including several core "stemness" genes (EBAF, TDGF1, and SOX2) and several downstream targets of WNT, NODAL, and FGF signaling (FGF4, NODAL, and ZFP42). Our results indicate that 12p gain is a functionally relevant change leading to activation of proliferation and reestablishment/maintenance of stem cell function through activation of key stem cell genes. Furthermore, the differential expression of core stem cell genes may explain the differences in pluripotency between embryonal carcinomas and seminomas. ©2006 American Association for Cancer Research.
Keywords:	human tissue; unclassified drug; gene cluster; human cell; cell proliferation; gene; gene targeting; gene expression profiling; down-regulation; genetic association; genetic variability; in vivo study; cell differentiation; stem cell; gene expression regulation; microarray analysis; oligonucleotide array sequence analysis; nucleotide sequence; tumor protein; testicular neoplasms; stem cell gene therapy; neoplasms, germ cell and embryonal; pluripotent stem cell; pluripotent stem cells; glucose transporter 3; germ cell tumor; wnt protein; transcription factor sox2; choriocarcinoma; seminoma; fibroblast growth factor; chromosome 12p; non seminomatous germinoma; multigene family; ccnd2 gene; chromosomes, human, pair 12; carcinoma, embryonal; protein nodal; protein ccnd2; protein ebaf; protein flj22028; protein rea; protein tdgf1; protein zfp42; flj22028 gene; gdf3 gene; glut3 gene; nanog gene; rea gene; stella gene; stem cell gene
Journal Title:	Cancer Research
Volume:	66
Issue:	2
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Date Published:	2006-01-15
Start Page:	820
End Page:	827
Language:	English
DOI:	10.1158/0008-5472.can-05-2445
PUBMED:	16424014
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-31544440121&partnerID=40&md5=c622a56bff83093796c785cf96540fda
Notes:	--- - "Cited By (since 1996): 108" - "Export Date: 4 June 2012" - "CODEN: CNREA" - "Source: Scopus"

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