Retinoic acid represses a cassette of candidate pluripotency chromosome 12p genes during induced loss of human embryonal carcinoma tumorigenicity.
Testicular germ cell tumors (TGCTs) are the most common carcinomas of young men aged 15-35. The molecular events involved in TGCT genesis are poorly understood. TGCTs have near universal amplification of the short arm of chromosome 12, however positional cloning efforts have not identified causative genes on 12p involved in formation or progression of TGCTs. Human embryonal carcinoma (EC) are the stem cells of TGCTs and are pluripotent. EC cells terminally differentiate toward a neuronal lineage with all-trans retinoic acid (RA) treatment resulting in a concomitant G1 cell cycle arrest and loss of tumorigenicity. Our efforts to define the molecular mechanisms of RA-mediated tumor cell differentiation at a critical "commitment to differentiate" window has identified a cassette of genes on 12p that are repressed with RA precisely as EC cells lose tumorigenic potential. These are Nanog, CD9, EDR1 (PHC1), SCNN1A, GDF3, Glut3 and Stella. The master pluripotency regulator Oct4 is located on chromosome 6 and is also repressed by RA. Notably, knockdown of Oct4 with siRNA results in repression of basal Nanog, EDR1, GDF3 and Stella gene expression. Nanog has recently been identified to play a role in maintenance of the pluripotency of mouse embryonic stem cells and CD9, EDR1, GDF3, and Stella have each been implicated as stem cell markers. Since RA suppresses the tumorigenicity of EC cells, these genes may have a critical role in the etiology of TGCTs, suggesting a link between enforced pluripotency and transformation.
Giuliano
Caryl J
CJ
Department of Pharmacology and Toxicology, 7650 Remsen, Dartmouth Medical School, Dartmouth Hitchcock-Medical Center, Hanover, NH 03755, USA.
Kerley-Hamilton
Joanna S
JS
Bee
Tom
T
Freemantle
Sarah J
SJ
Manickaratnam
Ranjan
R
Dmitrovsky
Ethan
E
Spinella
Michael J
MJ
D000293:Adolescent; D000328:Adult; D018236:Carcinoma, Embryonal / Q000503:physiopathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002881:Chromosomes, Human, Pair 12 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008297:Male; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D039904:Pluripotent Stem Cells / Q000187:drug effects / Q000502:physiology*; D034741:RNA, Small Interfering / Q000502:physiology; D013736:Testicular Neoplasms / Q000503:physiopathology; D014212:Tretinoin / Q000494:pharmacology*
D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D034741:RNA, Small Interfering; D014212:Tretinoin