Epstein-Barr virus Rta promotes invasion of bystander tumor cells through paracrine of matrix metalloproteinase 9

Highlights: • Rta-expressing cells promote invasion of bystander tumor cells through paracrine. • Rta upregulates MMP9 expression through activation of E2F. • The Rta-induced, paracrine-mediated pro-invasive effect is blocked upon knockdown or inhibition of MMP9. Clinical studies suggest a positive association between malignant progression of nasopharyngeal carcinoma (NPC) and Rta, a transcription factor of Epstein-Barr virus (EBV). However, Rta induces cellular senescence in vitro. To provide an underlying mechanism integrating these clues, we adapted a concept of senescence-associated secretory phenotype (SASP), based on which senescent cells facilitate tumor progression through paracrine. First, Rta-expressing NPC cells themselves show reduced invasiveness but promote invasion of Rta-negative tumor cells through secreted factors. Secretion of matrix metalloproteinase 9 (MMP9), an SASP protein, is increased by Rta, which requires the C-terminus of Rta and Rta-induced activation of E2F. Furthermore, the Rta-induced, paracrine-mediated pro-invasive effect is blocked upon knockdown of MMP9 expression or treatment with an MMP9 inhibitor. This study not only indicates that Rta can contribute to NPC progression through paracrine but also supports that MMP9 is a potential therapeutic target to prevent NPC metastasis.