STAT3 activation contributes directly to Epstein-Barr virus-mediated invasiveness of nasopharyngeal cancer cells in vitro.
Nasopharyngeal cancer (NPC) is an Epstein-Barr virus (EBV)-associated head and neck cancer prevalent in Asia. Although with reasons not fully understood, the intrinsic invasiveness of NPC is believed to be EBV-linked. Recently, EBV was found to induce STAT3 activation. Constitutive STAT3 activation correlated with advanced clinical staging in NPC. We hypothesized that STAT3 activation by EBV directly contributes to the intrinsic invasiveness of NPC cells. Phospho-STAT3-Tyr705 was detected in high percentage of NPC tumors (7/10 cases). Using a paired NPC cell line model, HONE-1 and the EBV-infected counterpart, HONE-1-EBV, we found that HONE-1-EBV expressed a higher level of phospho-STAT3-Tyr705 and was approximately 11-fold more invasive than HONE-1. In HONE-1-EBV, STAT3 siRNA targeting inhibited both spontaneous and serum-induced invasion, as well as cell growth. Conversely, activation of STAT3 (by expressing an activated STAT3 mutant, namely STAT3C) in the parental HONE-1, mimicking EBV-induced STAT3 activation, significantly enhanced its invasiveness and proliferation, which was accompanied by increased expression of markers of mesenchymal status, proliferation and anti-apoptosis. Our results demonstrated that EBV-induced STAT3 activation is responsible for NPC cell proliferation and invasion. This was further confirmed by a small molecule inhibitor of JAK/STAT3, JSI-124. JSI-124 inhibited STAT3 activation in HONE-1-EBV, with subsequent growth inhibition, induction of PARP cleavage, abrogation of anchorage-independent growth and invasion. We found that EBV-independent activation of STAT3 by a growth factor, EGF, also contributed to NPC invasion. In conclusion, EBV-induced STAT3 activation directly contributes to the intrinsic invasiveness of NPC cells and STAT3 targeting may be beneficial in treating aggressive NPC.
Lui
Vivian Wai Yan
VW
Cancer Signaling Laboratory, State Key Laboratory of Oncology in South China, Department of Clinical Oncology, Sir YK Pao Center for Cancer, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
Wong
Elaine Yue Ling
EY
Ho
Yeung
Y
Hong
Bo
B
Wong
Sze Chuen Cesar
SC
Tao
Qian
Q
Choi
Gigi Ching Gee
GC
Au
Thomas Chi Chuen
TC
Ho
Kakiu
K
Yau
Daisy Mei Sze
DM
Ma
Brigette Buig Yue
BB
Hui
Edwin Pun
EP
Chan
Andrew Sai-Kit
AS
Tsang
Chi-Man
CM
Tsao
Sai-Wah
SW
Grandis
Jennifer Rubin
JR
Chan
Anthony Tak-Cheung
AT
D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D003114:Colony-Forming Units Assay; D004338:Drug Combinations; D004815:Epidermal Growth Factor / Q000494:pharmacology; D020031:Epstein-Barr Virus Infections / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D006801:Humans; D007797:Laminin / Q000378:metabolism; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D009361:Neoplasm Invasiveness; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C059485:matrigel; D004815:Epidermal Growth Factor; D003094:Collagen