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Blood, 1 January 2008, Vol. 111, No. 1, pp. 292-301.
Prepublished online as a Blood First Edition Paper on August 24, 2007; DOI 10.1182/blood-2006-11-059881.
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NEOPLASIA
Down-regulation of the TGF-beta target gene, PTPRK, by the Epstein-Barr virus–encoded EBNA1 contributes to the growth and survival of Hodgkin lymphoma cells
Joanne R. Flavell1,
Karl R. N. Baumforth1,
Victoria H. J. Wood1,
Gillian L. Davies1,
Wenbin Wei1,
Gary M. Reynolds2,
Susan Morgan1,
Andrew Boyce1,
Gemma L. Kelly1,
Lawrence S. Young1, and
Paul G. Murray1
1 Cancer Research UK Institute for Cancer Studies and
2 Liver Research Laboratories, Medical School, University of Birmingham, Birmingham, United Kingdom
The Epstein-Barr virus (EBV) contributes to the growth and survival of Hodgkin lymphoma (HL) cells. Here we report that down-regulation of the transforming growth factor-beta (TGF-beta) target gene, protein tyrosine phosphatase receptor kappa (PTPRK), followed EBV infection of HL cells and was also more frequently observed in the Hodgkin and Reed-Sternberg (HRS) cells of EBV-positive compared with EBV-negative primary HL. The viability and proliferation of EBV-positive HL cells was decreased by overexpression of PTPRK, but increased following the knockdown of PTPRK expression in EBV-negative HL cells, demonstrating that PTPRK is a functional tumor suppressor in HL. EBV suppressed the TGF-beta–mediated activation of PTPRK expression, suggesting disruption of TGF-beta signaling upstream of PTPRK. This was confirmed when we showed that the Epstein-Barr nuclear antigen-1 (EBNA1) decreased Smad2 protein levels and that this was responsible for PTPRK down-regulation. EBNA1 decreased the half-life of Smad2 but did not interact with Smad2. By down-regulating Smad2 protein expression, EBNA1 apparently disables TGF-beta signaling, which subsequently decreases transcription of the PTPRK tumor suppressor. We speculate that loss of the phosphatase function of PTPRK may activate as-yet-unidentified growth-promoting protein tyrosine kinases, which in turn contribute to the pathogenesis of EBV-positive HL.
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