Dominant expression of survival signals of endoplasmic reticulum stress response in Hodgkin lymphoma.
The accumulation of viral proteins in endoplasmic reticulum (ER) may cause ER stress responses and lead to either apoptosis or survival depending on the driving signals. The strong expression of latent membrane protein-1 (LMP1) in Epstein-Barr virus (EBV)-positive Hodgkin lymphoma (HL) cells raises the question whether LMP1-induced ER stress response is associated with the characteristic tumor biology in HL. In this study, we investigated the expression of ER stress signals (glucose-regulated protein 78 [GRP78], X-box binding protein 1 [XBP1], activating transcription factor 6 [ATF6], CCAAT enhance-binding protein homologous protein [CHOP] and phospho-apoptosis signal-regulating kinase 1 [pASK1]) on 156 cases of HL. Furthermore, LMP1 transfection on EBV-negative HL cell lines was used to explore the regulation of ER stress signals by EBV-LMP1. Interestingly, we demonstrated that the survival signals of ER stress response (GRP78, 62%; XBP1u [unspliced], 55%; XBP1s [spliced], 38%; ATF6, 91%) were dominantly expressed over the ER death signals (CHOP, 10%; pASK1, 7%) in all histological subtypes of HL with a similar level in both EBV-positive and EBV-negative cases. However, expression of ER signals did not bear prognostic significance. In vitro, LMP1 transfection increased the expression of GRP78 and XBP1, but attenuated the expression of death signals, CHOP and pASK1. These data indicate that EBV-LMP1 may play a role in shifting EBV-infected cells towards the survival pathway in the presence of ER stress in EBV-positive HL cases.
Department of Pathology, National Cheng Kung University and Hospital, Tainan, Taiwan.
Kung-Chao
KC
Chang
Paul C-H
PC
Chen
Ya-Ping
YP
Chen
Yao
Y
Chang
Ih-Jen
IJ
Su
D051702:Activating Transcription Factor 6 / Q000032:analysis; D000328:Adult; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000032:analysis; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006360:Heat-Shock Proteins / Q000032:analysis; D006689:Hodgkin Disease / Q000401:mortality* / Q000473:pathology / Q000821:virology; D006801:Humans; D008297:Male; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000032:analysis; D014763:Viral Matrix Proteins / Q000502:physiology; D000071717:X-Box Binding Protein 1
C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D014763:Viral Matrix Proteins; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human