Epstein-Barr Virus-Encoded LMP2A Induces an Epithelial–Mesenchymal Transition and Increases the Number of Side Population Stem-like Cancer Cells in Nasopharyngeal Carcinoma

PLoS Pathogens

Jing-Yan Cao¹  Xing Zhang²  Yi-Xin Zeng²  Li-Hua Xu²  Yun-Fei Xia²  Jian-Yong Shao²  Li-Juan Hu²  Hai-Qiang Mai²  Dan Xiong²  Man-Zhi Li³  Li-Bing Song³  Qiu-Yan Chen³  Bao-Hong Guo³  Yi-Jun Huang³  Chao-Nan Qian³  Mu-Sheng Zeng³  Qing-Li Kong³  Yi Liang³  Su Guan⁴ 

[1] Affiliated Hospital of Jining Medical College, Shandong, People's Republic of China;Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China;State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China;Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China

关键词: Nasopharyngeal carcinoma;    Epstein-Barr virus;    Mouse models;    Tumor stem cells;    Reverse transcriptase-polymerase chain reaction;    Epithelial cells;    Invasive tumors;    Stem cell lines;   

DOI  :  10.1371/journal.ppat.1000940

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

It has been recently reported that a side population of cells in nasopharyngeal carcinoma (NPC) displayed characteristics of stem-like cancer cells. However, the molecular mechanisms underlying the modulation of such stem-like cell populations in NPC remain unclear. Epstein-Barr virus was the first identified human tumor virus to be associated with various malignancies, most notably NPC. LMP2A, the Epstein-Barr virus encoded latent protein, has been reported to play roles in oncogenic processes. We report by immunostaining in our current study that LMP2A is overexpressed in 57.6% of the nasopharyngeal carcinoma tumors sampled and is mainly localized at the tumor invasive front. We found also in NPC cells that the exogenous expression of LMP2A greatly increases their invasive/migratory ability, induces epithelial–mesenchymal transition (EMT)-like cellular marker alterations, and stimulates stem cell side populations and the expression of stem cell markers. In addition, LMP2A enhances the transforming ability of cancer cells in both colony formation and soft agar assays, as well as the self-renewal ability of stem-like cancer cells in a spherical culture assay. Additionally, LMP2A increases the number of cancer initiating cells in a xenograft tumor formation assay. More importantly, the endogenous expression of LMP2A positively correlates with the expression of ABCG2 in NPC samples. Finally, we demonstrate that Akt inhibitor (V) greatly decreases the size of the stem cell side populations in LMP2A-expressing cells. Taken together, our data indicate that LMP2A induces EMT and stem-like cell self-renewal in NPC, suggesting a novel mechanism by which Epstein-Barr virus induces the initiation, metastasis and recurrence of NPC.

【 授权许可】

CC BY