Endoplasmic reticulum stress triggers XBP-1-mediated up-regulation of an EBV oncoprotein in nasopharyngeal carcinoma.
Endoplasmic reticulum (ER) stress-activated unfolded protein response (UPR) plays multiple roles in cancer development, but its specific roles for virus-associated cancers have not been fully understood. It is still unknown whether ER stress/UPR occurs in and contributes to nasopharyngeal carcinoma (NPC), an epithelial malignancy closely associated with EBV. Here, we report that UPR proteins are frequently detected in NPC biopsies. In addition, we reveal that, in EBV-infected NPC cells, ER stress inducers up-regulate a potent EBV oncoprotein latent membrane protein 1 (LMP1), and the ER stress-induced LMP1 enhances production of interleukin-8. ER stress triggers LMP1 expression at a transcriptional level, activating a distal LMP1 promoter TR-L1. TR-L1 contains an ER stress-responsive element, which is targeted by an UPR protein XBP-1. Ectopic expression of XBP-1 induces LMP1 expression, and knockdown of XBP-1 blocks ER stress-triggered up-regulation of LMP1 in NPC cells. Furthermore, XBP-1 significantly correlates with LMP1 expression in NPC tumor biopsies. Therefore, this study not only provides a novel clue linking ER stress/UPR to EBV-associated NPC but also suggests that ER stress/UPR can promote virus-associated cancer in a unique way by driving expression of a viral oncogene.
Department of Otolaryngology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Jenn-Ren
JR
Hsiao
Kung-Chao
KC
Chang
Chaio-Wei
CW
Chen
Shih-Yi
SY
Wu
Ih-Jen
IJ
Su
Mei-Chi
MC
Hsu
Ying-Tai
YT
Jin
Sen-Tien
ST
Tsai
Kenzo
K
Takada
Yao
Y
Chang
D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000473:pathology*; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D010957:Plasmids; D011489:Protein Denaturation; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics; D000071717:X-Box Binding Protein 1
D002843:Chromatin; D017931:DNA Primers; D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D014763:Viral Matrix Proteins; D014764:Viral Proteins; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human