STAT3 activation contributes directly to Epstein‐Barr virus–mediated invasiveness of nasopharyngeal cancer cells in vitro

• Published in: International journal of cancer Vol. 125; no. 8; pp. 1884 - 1893
• Main Authors: Lui, Vivian Wai Yan, Wong, Elaine Yue Ling, Ho, Yeung, Hong, Bo, Wong, Sze Chuen Cesar, Tao, Qian, Choi, Gigi Ching Gee, Au, Thomas Chi Chuen, Ho, Kakiu, Yau, Daisy Mei Sze, Ma, Brigette Buig Yue, Hui, Edwin Pun, Chan, Andrew Sai‐Kit, Tsang, Chi‐Man, Tsao, Sai‐Wah, Grandis, Jennifer Rubin, Chan, Anthony Tak‐Cheung
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15-10-2009; Wiley-Blackwell
• Subjects: Biological and medical sciences; Blotting, Western; Cell Adhesion; Cell Movement; Cell Proliferation; Collagen - metabolism; Colony-Forming Units Assay; Drug Combinations; EBV; Epidermal Growth Factor - pharmacology; Epstein-Barr virus; Epstein-Barr Virus Infections - metabolism; Epstein-Barr Virus Infections - pathology; Epstein-Barr Virus Infections - virology; Herpesvirus 4, Human - pathogenicity; Humans; invasion; Laminin - metabolism; Medical sciences; nasopharyngeal cancer (NPC); Nasopharyngeal Neoplasms - metabolism; Nasopharyngeal Neoplasms - pathology; Nasopharyngeal Neoplasms - virology; Neoplasm Invasiveness; Otorhinolaryngology. Stomatology; Proteoglycans - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - pharmacology; STAT3; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Tumor Cells, Cultured; Tumors; Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology; Gammaherpesvirinae; Human; Nasopharynx cancer; Herpesviridae; nasopharyngeal cancer (NPC); STAT3; Epstein Barr virus; Malignant tumor; Metastasis; In vitro; Invasion; Infection; Virus; Cancerology; Viral disease; Transcription factor STAT3; EBV; ENT disease; Pharynx disease; Cancer
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.24567

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 ∼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. © 2009 UICC