The Oct-3/4 transcription factor sustains embryonic stem (ES) cell self-renewal and is a dose-dependent cell fate determinant. In the adult male, its expression is restricted to type A spermatogonia. We show that Oct-3/4 is expressed in all human testicular germ cell tumors (GCTs) tested, even in the early premalignant component. We demonstrate that Oct-3/4 dictates ES cells' oncogenic potential in a dose-dependent manner; high levels increase the malignant potential of ES cell-derived tumors while Oct-3/4 inactivation induces regression of the malignant component. Oct-3/4 expression in a heterologous cell system transforms nontumorigenic cells and endows tumorigenicity in nude mice. Our findings suggest that Oct-3/4 is not only a distinctive immunohistochemical marker for GCTs, but also plays a critical role in the genesis of these tumors.
Bibliographical noteFunding Information:
We thank Drs. Austin G. Smith for the wt CGR8 ES cells, ZHTc25, ZHTc6, and ZHBTc4 ES cells; Maria Alessandra Vigano for V-P Oct-3/4 expression plasmid; William C. Hahn for the pBp-Ras expression vector; Graeme I. Bell for the human Oct-3/4 cDNA clone; Mario Baras and Norman Grover for statistical analyses; and Ada Hatzubai for helping to raise the polyclonal rabbit anti-sera directed against the human and mouse Oct-3/4 proteins. We also thank Shafika Kasem for helping with the immunohistochemistry assays and Nirit Feldman and Ariela Gerzon for helping with the mice care. We thank Dr. Ilan Hammel for his help with the systematic analysis of our histological sections and Drs. Austin G. Smith and Karen Meir for stimulating discussions and a constructive critical reading of the manuscript. This work was supported by research grants from the Israel Cancer Research Fund (to E.P.), the Public Committee for the Designation of Estate Funds (to E.P. and Y.B.), and the Israel Science Foundation (to Y.B.).