Function of EWS-POU5F1 in sarcomagenesis and tumor cell maintenance.
POU5F1 is a transcription factor essential for the self-renewal activity and pluripotency of embryonic stem cells and germ cells. We have previously reported that POU5F1 is fused to EWSR1 in a case of undifferentiated sarcoma with chromosomal translocation t(6;22)(p21;q12). In addition, the EWS-POU5F1 chimeras have been recently identified in human neoplasms of the skin and salivary glands. To clarify the roles of the EWS-POU5F1 chimera in tumorigenesis and tumor cell maintenance, we used small-interfering RNA-mediated gene silencing. Knockdown of EWS-POU5F1 in the t(6;22) sarcoma-derived GBS6 cell line resulted in a significant decrease of cell proliferation because of G1 cell cycle arrest associated with p27(Kip1) up-regulation. Moreover, senescence-like morphological changes accompanied by actin polymerization were observed. In contrast, EWS-POU5F1 down-regulation markedly increased the cell migration and invasion as well as activation of metalloproteinase 2 and metalloproteinase 14. The results indicate that the proliferative activity of cancer cells and cell motility are discrete processes in multistep carcinogenesis. These findings reveal the functional role of the sarcoma-related chimeric protein as well as POU5F1 in the development and progression of human neoplasms.
Fujino
Takashi
T
Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
Nomura
Kimie
K
Ishikawa
Yuichi
Y
Makino
Hatsune
H
Umezawa
Akihiro
A
Aburatani
Hiroyuki
H
Nagasaki
Koichi
K
Nakamura
Takuro
T
D045744:Cell Line, Tumor; D002465:Cell Movement; D016922:Cellular Senescence; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis* / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D034802:RNA-Binding Protein EWS / Q000096:biosynthesis* / Q000235:genetics*; D012509:Sarcoma / Q000378:metabolism / Q000473:pathology*; D012878:Skin Neoplasms / Q000473:pathology
C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D034741:RNA, Small Interfering; D034802:RNA-Binding Protein EWS; D050760:Cyclin-Dependent Kinase Inhibitor p27