TY - JOUR
T1 - Role of SOX2 in the etiology of embryonal carcinoma, based on analysis of the NCCIT and NT2 cell lines
AU - Eini, Ronak
AU - Stoop, Hans
AU - Gillis, Ad J M
AU - Biermann, Katharina
AU - Dorssers, Lambert C J
AU - Looijenga, Leendert H J
PY - 2014
Y1 - 2014
N2 - The transcription factor SOX2, associated with amongst others OCT3/4, is essential for maintenance of pluripotency and self-renewal of embryonic stem cells. SOX2 is highly expressed in embryonal carcinoma (EC), the stem cell component of malignant nonseminomatous germ cell tumors, referred to as germ cell cancer (GCC). In fact, OCT3/4 together with SOX2 is an informative diagnostic tool for EC in a clinical setting. Several studies support the hypothesis that SOX2 is a relevant oncogenic factor in various cancers and recently, SOX2 has been suggested as a putative therapeutic target for early stage EC. We demonstrate the presence of genomic amplification of SOX2 in an EC cell line, NCCIT, using array comparative genome hybridization and fluorescence in situ hybridization. Down-regulation of SOX2 by targeted siRNA provokes NCCIT cells towards apoptosis, while inhibition of OCT3/4 expression induced differentiation, with retained SOX2 levels. Mice pluripotent xenografts from NCCIT (N-NCCIT and N2-NCCIT) show a consistent SOX2 expression, in spite of loss of the expression of OCT3/4, and differentiation, with retained presence of genomic amplification. No SOX2 amplification has been identified in primary pure and mixed EC in vivo patient samples so far. The data presented in this study are based on a single EC cell line with a SOX2 amplification, with NT2 as control EC cell line, showing no profound induction of apoptosis upon SOX2 downregulation. The findings are of relevance to identify mechanisms involved in the pathogenesis of EC tumors, and support the model of SOX2-oncogene dependency of EC, which however, does not exclude induction of differentiation. This finding is likely related to the presence of wild type p53 in GCC, resulting in expression of downstream target genes, amongst others miR-34a, miR-145 and SOX2, associated to the unique sensitivity of GCC to DNA damaging agents.
AB - The transcription factor SOX2, associated with amongst others OCT3/4, is essential for maintenance of pluripotency and self-renewal of embryonic stem cells. SOX2 is highly expressed in embryonal carcinoma (EC), the stem cell component of malignant nonseminomatous germ cell tumors, referred to as germ cell cancer (GCC). In fact, OCT3/4 together with SOX2 is an informative diagnostic tool for EC in a clinical setting. Several studies support the hypothesis that SOX2 is a relevant oncogenic factor in various cancers and recently, SOX2 has been suggested as a putative therapeutic target for early stage EC. We demonstrate the presence of genomic amplification of SOX2 in an EC cell line, NCCIT, using array comparative genome hybridization and fluorescence in situ hybridization. Down-regulation of SOX2 by targeted siRNA provokes NCCIT cells towards apoptosis, while inhibition of OCT3/4 expression induced differentiation, with retained SOX2 levels. Mice pluripotent xenografts from NCCIT (N-NCCIT and N2-NCCIT) show a consistent SOX2 expression, in spite of loss of the expression of OCT3/4, and differentiation, with retained presence of genomic amplification. No SOX2 amplification has been identified in primary pure and mixed EC in vivo patient samples so far. The data presented in this study are based on a single EC cell line with a SOX2 amplification, with NT2 as control EC cell line, showing no profound induction of apoptosis upon SOX2 downregulation. The findings are of relevance to identify mechanisms involved in the pathogenesis of EC tumors, and support the model of SOX2-oncogene dependency of EC, which however, does not exclude induction of differentiation. This finding is likely related to the presence of wild type p53 in GCC, resulting in expression of downstream target genes, amongst others miR-34a, miR-145 and SOX2, associated to the unique sensitivity of GCC to DNA damaging agents.
KW - Animals
KW - Apoptosis/genetics
KW - Biomarkers, Tumor
KW - Carcinoma, Embryonal/genetics
KW - Cell Line, Tumor
KW - Disease Models, Animal
KW - Female
KW - Gene Amplification
KW - Gene Expression
KW - Gene Knockdown Techniques
KW - Gene Silencing
KW - Heterografts
KW - Humans
KW - Mice
KW - Models, Biological
KW - Octamer Transcription Factor-3/genetics
KW - RNA Interference
KW - SOXB1 Transcription Factors/genetics
UR - http://www.scopus.com/inward/record.url?scp=84896771544&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0083585
DO - 10.1371/journal.pone.0083585
M3 - Article
C2 - 24404135
SN - 1932-6203
VL - 9
SP - e83585
JO - PloS one
JF - PloS one
IS - 1
M1 - e83585
ER -