Nuclear factor kappaB-dependent gene expression profiling of Hodgkin's disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcription 5a activity.
Constitutive nuclear nuclear factor (NF)-kappaB activity is observed in a variety of hematopoietic and solid tumors. Given the distinctive role of constitutive NF-kappaB for Hodgkin and Reed-Sternberg (HRS) cell viability, we performed molecular profiling in two Hodgkin's disease (HD) cell lines to identify NF-kappaB target genes. We recognized 45 genes whose expression in both cell lines was regulated by NF-kappaB. The NF-kappaB-dependent gene profile comprises chemokines, cytokines, receptors, apoptotic regulators, intracellular signaling molecules, and transcription factors, the majority of which maintain a marker-like expression in HRS cells. Remarkably, we found 17 novel NF-kappaB target genes. Using chromatin immunoprecipitation we demonstrate that NF-kappaB is recruited directly to the promoters of several target genes, including signal transducer and activator of transcription (STAT)5a, interleukin-13, and CC chemokine receptor 7. Intriguingly, NF-kappaB positively regulates STAT5a expression and signaling pathways in HRS cells, and promotes its persistent activation. In fact, STAT5a overexpression was found in most tumor cells of tested patients with classical HD, indicating a critical role for HD. The gene profile underscores a central role of NF-kappaB in the pathogenesis of HD and potentially of other tumors with constitutive NF-kappaB activation.
Hinz
Michael
M
Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
Lemke
Petra
P
Anagnostopoulos
Ioannis
I
Hacker
Christine
C
Krappmann
Daniel
D
Mathas
Stephan
S
Dörken
Bernd
B
Zenke
Martin
M
Stein
Harald
H
Scheidereit
Claus
C
D001483:Base Sequence; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D006689:Hodgkin Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008894:Milk Proteins; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D016539:Reed-Sternberg Cells / Q000378:metabolism / Q000473:pathology; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins