Stem-cell protein Piwil2 is widely expressed in tumors and inhibits apoptosis through activation of Stat3/Bcl-XL pathway

• Published in: Human molecular genetics Vol. 15; no. 2; pp. 201 - 211
• Main Authors: Lee, Jae Ho, Schütte, Dorothea, Wulf, Gerald, Füzesi, Laszlo, Radzun, Heinz-Joachim, Schweyer, Stephan, Engel, Wolfgang, Nayernia, Karim
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.01.2006; Oxford Publishing Limited (England)
• Subjects: Ageing, cell death; Animals; Apoptosis - genetics; Argonaute Proteins; bcl-X Protein - metabolism; Biological and medical sciences; Blotting, Northern; Blotting, Western; Cell physiology; DNA Primers; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Genetics of eukaryotes. Biological and molecular evolution; Humans; Immunohistochemistry; Male; Mice; Molecular and cellular biology; NIH 3T3 Cells; Proteins - genetics; Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Seminoma - metabolism; Signal Transduction; STAT3 Transcription Factor - metabolism; Testicular Neoplasms - metabolism; Regulation(control); Stem cell; Genetics; Tumor; Activation; Gene expression; Protein; Apoptosis
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddi430

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 non-seminomatous tumors. Expression of the Piwil2 gene was also found 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 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 signaling pathway. Expression of Piwil2 in a wide variety of tumors could be a useful prognostic factor that could have also diagnostic and therapeutic implications.