Abnormal PcG protein expression in Hodgkin's lymphoma. Relation with E2F6 and NFkappaB transcription factors.
The Polycomb group (PcG) of proteins comprises a family of repressors of homeobox genes that play key roles in body formation, haematopoiesis and cell cycle control. In this study, a large-scale analysis of PcG protein expression (BMI1, MEL18, PH1, RNF2, RING1, and RYBP) was performed in 321 Hodgkin's lymphoma (HL) biopsies and in reactive lymphoid tissues using tissue microarrays. The relevance of PcG proteins in HL was also investigated by the simultaneous analysis of PcG and other proteins involved in the control of cell cycle, transcription machinery and lymphoid differentiation. The analysis revealed increased expression of a set of PcG proteins (particularly RYBP and BMI1) in tumour cells in comparison with reactive lymphoid tissue. One of the most striking findings was anomalous RYBP expression in 55% of classical HL cases associated with an unfavourable response to treatment and shorter survival. The data obtained in this study also show an association of PcG proteins with E2F6 and NFkappaB transcription factors. The statistical relationship between PcG and NFkappaB activation was further explored in HL-derived cell lines treated with curcumin, an NFkappaB inhibitor, and TNFalpha. Up- or downregulation of MEL18 was paralleled by loss or gain of activated NFkappaB, which suggests that NFkappaB may regulate expression of this protein. Investigation of the relationship between E2F6 and RING1 by immunofluorescence and confocal analysis, in HL cell lines and paraffin sections, revealed co-expression of both proteins in the same tumour cells. These results allow us to propose that the formation of transcription complexes with E2F6 may modify the functional status of PcG proteins in HSR cells.
Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), C/Melchor Fernández Almagro 3, E-28029 Madrid, Spain. msbeato@cnio.es
Margarita
M
Sánchez-Beato
Esther
E
Sánchez
Juan F
JF
García
Alberto
A
Pérez-Rosado
María C
MC
Montoya
Mario
M
Fraga
M Jesús
MJ
Artiga
Mercedes
M
Navarrete
Víctor
V
Abraira
Manuel
M
Morente
Manel
M
Esteller
Haruhiko
H
Koseki
Miguel
M
Vidal
Miguel A
MA
Piris
D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D050684:E2F Transcription Factors; D050701:E2F6 Transcription Factor; D019075:Electrophoresis, Capillary / Q000379:methods; D005455:Fluorescent Antibody Technique / Q000379:methods; D006689:Hodgkin Disease / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D008221:Lymphoid Tissue / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics*; D009687:Nuclear Proteins / Q000032:analysis; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins / Q000032:analysis; D012097:Repressor Proteins / Q000032:analysis*; D014157:Transcription Factors / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases; D016335:Zinc Fingers
C069077:BMI1 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050701:E2F6 Transcription Factor; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; C489348:PCGF2 protein, human; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; C434957:RYBP protein, human; D012097:Repressor Proteins; D014157:Transcription Factors; D063150:Polycomb Repressive Complex 1; C080355:RING1 protein, human; C489841:RNF2 protein, human; D044767:Ubiquitin-Protein Ligases