Retinoic acid represses a cassette of candidate pluripotency chromosome 12p genes during induced loss of human embryonal carcinoma tumorigenicity

Caryl J. Giuliano, Joanna S. Kerley-Hamilton, Tom Bee, Sarah J. Freemantle, Ranjan Manickaratnam, Ethan Dmitrovsky, Michael J. Spinella

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)48-56
Number of pages9
JournalBiochimica et Biophysica Acta - Gene Structure and Expression
Volume1731
Issue number1
DOIs
StatePublished - Oct 15 2005
Externally publishedYes

Keywords

  • Cancer stem cell
  • Embryonal carcinoma
  • Germ cell tumor
  • Oct4
  • Pluripotency
  • Tumorigenicity

ASJC Scopus subject areas

  • Structural Biology
  • Biophysics
  • Biochemistry
  • Genetics

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