Epstein-Barr virus-encoded LMP2A induces an epithelial-mesenchymal transition and increases the number of side population stem-like cancer cells in nasopharyngeal carcinoma.
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.
State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.
Qing-Li
QL
Kong
Li-Juan
LJ
Hu
Jing-Yan
JY
Cao
Yi-Jun
YJ
Huang
Li-Hua
LH
Xu
Yi
Y
Liang
Dan
D
Xiong
Su
S
Guan
Bao-Hong
BH
Guo
Hai-Qiang
HQ
Mai
Qiu-Yan
QY
Chen
Xing
X
Zhang
Man-Zhi
MZ
Li
Jian-Yong
JY
Shao
Chao-Nan
CN
Qian
Yun-Fei
YF
Xia
Li-Bing
LB
Song
Yi-Xin
YX
Zeng
Mu-Sheng
MS
Zeng
D000818:Animals; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D016022:Case-Control Studies; D002448:Cell Adhesion; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D003114:Colony-Forming Units Assay; D004847:Epithelial Cells / Q000473:pathology / Q000821:virology; D020031:Epstein-Barr Virus Infections / Q000378:metabolism / Q000821:virology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D008648:Mesoderm / Q000473:pathology* / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
D014408:Biomarkers, Tumor; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D012333:RNA, Messenger; D014763:Viral Matrix Proteins