Functional evidence that the self-renewal gene NANOG regulates human tumor development.
Tumor development has long been known to resemble abnormal embryogenesis. The embryonic stem cell (ESC) self-renewal gene NANOG is purportedly expressed by some epithelial cancer cells but a causal role in tumor development has remained unclear. Here, we provide compelling evidence that cultured cancer cells, as well as xenograft- and human primary prostate cancer cells express a functional variant of NANOG. NANOG mRNA in cancer cells is derived predominantly from a retrogene locus termed NANOGP8. NANOG protein is detectable in the nucleus of cancer cells and is expressed higher in patient prostate tumors than matched benign tissues. NANOGP8 mRNA and/or NANOG protein levels are enriched in putative cancer stem/progenitor cell populations. Importantly, extensive loss-of-function analysis reveals that RNA interference-mediated NANOG knockdown inhibits tumor development, establishing a functional significance for NANOG expression in cancer cells. Nanog short hairpin RNA transduced cancer cells exhibit decreased long-term clonal and clonogenic growth, reduced proliferation and, in some cases, altered differentiation. Thus, our results demonstrate that NANOG, a cell-fate regulatory molecule known to be important for ESC self-renewal, also plays a novel role in tumor development.
Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Science Park-Research Division, Smithville, TX 78957, USA.
Collene R
CR
Jeter
Mark
M
Badeaux
Grace
G
Choy
Dhyan
D
Chandra
Lubna
L
Patrawala
Can
C
Liu
Tammy
T
Calhoun-Davis
Holm
H
Zaehres
George Q
GQ
Daley
Dean G
DG
Tang
D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002999:Clone Cells; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008297:Male; D000071317:Nanog Homeobox Protein; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D011544:Pseudogenes; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic; D014161:Transduction, Genetic
D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D012333:RNA, Messenger; D034741:RNA, Small Interfering