NPC-TW01中的BGLF4重複表達提升細胞侵襲和移動能力

Abstract

Epstein-Barr virus (EBV) is a human gamma-herpesvirus. Previous studies of nasopharyngeal carcinoma (NPC) serology indicates that recurrent EBV reactivation is highly correlated with NPC development and in the mouse xenograft model, recurrent EBV reactivation was demonstrated to increase tumorigenicity and metastasis ability of cell. Among viral lytic proteins, EBV DNase was reported to induce host cell genome instability and potentially increases tumorigenicity of NPC cells. Considering that other lytic proteins also have potential oncogenic function, we investigated further about the potential oncogenic role of BGLF4 during virus recurrent reactivation in NPC cells. EBV BGLF4 is a serine/threonine protein kinase that has a broad-spectrum viral and cellular substrates. At the late stage of virus replication, BGLF4 induces partial nuclear lamina disassembly through a cellular CDK1-mimicking pathway. In addition, BGLF4 induces nucleus shape alteration and cytoskeleton rearrangement. Considering the regulatory role of nucleus and cytoskeleton in cell migration, we adopt inverted transwell and boyden chamber with different pore size to examine the influence of repetitive BGLF4 expression on cell invasiveness and motility. We demonstrate that repetitive expression of BGLF4 increases invasiveness and motility of NPC-TW01 cells. Also, repetitive BGLF4 expression contributes to a loosen nuclear lamina in cells and hence promotes cell migrates through a narrow space in a size smaller than the cell nucleus. Moreover, BGLF4 redistributes E-cadherin and induces F-actin protrusion formation at cell margin which may contribute to cell migration in a 3D environment. In conclusion, we prove that repetitive BGLF4 expression increase cell invasiveness and motility that may promote tumor metastasis.