Epstein-Barr virus latent membrane protein-1 upregulates autophagy and promotes viability in Hodgkin lymphoma: Implications for targeted therapy.

Abstract

Hodgkin lymphoma (HL) is composed of neoplastic Hodgkin and Reed-Sternberg cells in an inflammatory background. The neoplastic cells are derived from germinal center B cells that, in most cases, are infected by Epstein-Barr virus (EBV), which may play a role in tumorigenesis. Given that EBV-latent membrane protein 1 (LMP1) regulates autophagy in B cells, we explored the role of autophagy mediated by EBV or LMP1 in HL. We found that EBV-LMP1 transfection in HL cells induced a modest increase in autophagy signals, attenuated starvation-induced autophagic stress, and alleviated autophagy inhibition- or doxorubicin-induced cell death. LMP1 knockdown leads to decreased autophagy LC3 signals. A xenograft mouse model further showed that EBV infection significantly increased expression of the autophagy marker LC3 in HL cells. Clinically, LC3 was expressed in 15% (19/127) of HL samples, but was absent in all cases of nodular lymphocyte-predominant and lymphocyte-rich classic HL cases. Although expression of LC3 was not correlated with EBV status or clinical outcome, autophagic blockade effectively eradicated LMP1-positive HL xenografts with better efficacy than LMP1-negative HL xenografts. Collectively, these results suggest that EBV-LMP1 enhances autophagy and promotes the viability of HL cells. Autophagic inhibition may be a potential therapeutic strategy for treating patients with HL, especially EBV-positive cases.

• Authors: Hui-Chen Lin, Yao Chang, Ruo-Yu Chen, Liang-Yi Hung, Paul Chih-Hsueh Chen, Ya-Ping Chen, L Jeffrey Medeiros, Po-Min Chiang, Kung-Chao Chang
• Journal: Cancer science (Cancer Sci) Vol. 112 Issue 4 Pg. 1589-1602 (Apr 2021) ISSN: 1349-7006 [Electronic] England
• PMID: 33525055 (Publication Type: Journal Article)
• Copyright: © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• EBV-associated membrane antigen, Epstein-Barr virus
• Viral Matrix Proteins
• Doxorubicin

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Animals
• Autophagy (genetics)
• Cell Death (genetics)
• Cell Line, Tumor
• Cell Survival (genetics)
• Child
• Child, Preschool
• Doxorubicin (therapeutic use)
• Epstein-Barr Virus Infections (pathology, virology)
• Female
• Germinal Center (drug effects)
• Herpesvirus 4, Human (genetics)
• Heterografts
• Hodgkin Disease (drug therapy, pathology, virology)
• Humans
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Middle Aged
• Up-Regulation (genetics)
• Viral Matrix Proteins (genetics)
• Young Adult