Human Molecular Genetics Advance Access published online on December 23, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi430
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1 Institute of Human Genetics, University of Göttingen, 37073 Göttingen, Germany
* To whom correspondence should be addressed. The genes of the piwi family are defined by conserved PAZ and Piwi domains and play important roles in stem cell self-renewal, RNA silencing, and translational regulation in various organisms. Both, mouse and human Piwil2 genes, members of the piwi gene family, are specifically expressed in testis. We report here enhanced expression of the human Piwil2 gene in testicular seminomas, but not in testicular nonseminomatous tumors. Expression of the Piwil2 gene was found also in different tumors examined, including prostate, breast, gastrointestinal, ovarian and endometrial cancer of human and in breast tumors, rhabdomyosarcoma and medulloblastoma of mouse. Therefore, Piwil2 can be categorized as a novel member of cancer/testis antigens. To identify genes activated by Piwil2, RNA isolated from NIH-3T3 cells expressing constitutively Piwil2 were compared with RNA samples from control NIH-3T3 cells using a cancer gene array. Induction of high level expression of the antiapoptotic gene Bcl-XL was observed in cells expressing Piwil2. Furthermore, increased Bcl-XL expression correlated with increase of signal transducer and activator of transcription 3 (Stat3) expression. Gene silencing of Piwil2 with its siRNA (small interference RNA) suppressed Stat3 and Bcl-XL expression and induced apoptosis. A causal link between Piwil2 expression and inhibition of apoptosis and enhanced proliferation was demonstrated in cells expressing Piwil2. Furthermore, results of soft agar assay indicated that Piwil2 overexpression induced transformation of fibroblast cells. In summary, our results demonstrate that Piwil2 is widely expressed in tumors and acts as an oncogene by inhibition of apoptosis and promotion of proliferation via Stat3/Bcl-XL signalling pathway. Expression of Piwil2 in a wide variety of tumors could be a useful prognostic factor that could have also diagnostic and therapeutic implications.
Received July 1, 2005
Accepted November 17, 2005
Article
Stem cell protein Piwil2 is widely expressed in tumors and inhibits apoptosis through activation of Stat3/Bcl-XL pathway
Jae Ho Lee 1,
Dorothea Schütte 1,
Gerald Wulf 2,
Laszlo Füzesi 3,
Heinz-Joachim Radzun 4,
Stephan Schweyer 4,
Wolfgang Engel 1,
and
Karim Nayernia 5 *
2 Department of Hematology and Oncology, University of Göttingen, 37073 Göttingen, Germany
3 Department of Gartroentropathology, University of Göttingen, 37073 Göttingen, Germany
4 Departments of Pathology, University of Göttingen, 37073 Göttingen, Germany
5 Institute of Human Genetics, University of Göttingen, Heinrich Düker Weg 12, 37073 Göttingen, Germany
Karim Nayernia, E-mail: knayern{at}gwdg.de
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