Research Institute of Immunobiology, Department of Medical Lifescience, College of Medicine, Catholic University of Korea, Seoul, 137-701, Korea.
Arch Pharm Res. 2011 Apr;34(4):635-43. doi: 10.1007/s12272-011-0414-7. Epub 2011 May 5.
Although Epstein-Barr virus (EBV) is associated with 6-16% of the gastric carcinoma (GC) cases, the effect of EBV infection on the tumorigenesis process and the responsiveness to chemotherapy remain unclear. We compared chemosensitivity of the EBV-positive GC (AGSEBV) and EBV-negative GC (AGS) cells to 5-fluorouracil (5-FU). Although 5-FU inhibited the growth of both cell lines in a dose- and time-dependent manner, the sensitivity of EBV-positive GC cells to 5-FU was lower than that of EBV-negative GC cells. The cleavage of PARP and caspase-3 was also lower in AGS-EBV cells than in AGS cells following 5-FU treatment. Both the level of Bcl-2 expression and the ratio of Bcl-2/Bax were higher in AGS-EBV than in AGS cells not only at basal state but also following 5-FU treatment. Moreover, p53 and p21 expression was enhanced further by 5-FU in AGS than in AGS-EBV cells. Immunofluorescence assay and Western blot showed that 5-FU induced the expression of EBV-lytic genes including BZLF1, BRLF1, BMRF1 and BHRF1. Our results suggest that latent and lytic EBV infection contributes to the chemoresistance to 5-FU in gastric carcinoma by modulating apoptosis related cellular genes.
虽然 Epstein-Barr 病毒 (EBV) 与 6-16%的胃癌 (GC) 病例有关，但 EBV 感染对肿瘤发生过程和化疗反应的影响仍不清楚。我们比较了 EBV 阳性胃癌 (AGSEBV) 和 EBV 阴性胃癌 (AGS) 细胞对 5-氟尿嘧啶 (5-FU) 的化疗敏感性。虽然 5-FU 以剂量和时间依赖的方式抑制两种细胞系的生长，但 EBV 阳性 GC 细胞对 5-FU 的敏感性低于 EBV 阴性 GC 细胞。5-FU 处理后，AGS-EBV 细胞中 PARP 和 caspase-3 的裂解也低于 AGS 细胞。5-FU 处理后，AGS-EBV 细胞中 Bcl-2 的表达水平和 Bcl-2/Bax 的比值不仅在基础状态下而且在 5-FU 处理后均高于 AGS 细胞。此外，p53 和 p21 的表达在 AGS 细胞中比在 AGS-EBV 细胞中被 5-FU 进一步增强。免疫荧光和 Western blot 显示，5-FU 诱导了 EBV 裂解基因的表达，包括 BZLF1、BRLF1、BMRF1 和 BHRF1。我们的结果表明，潜伏和裂解性 EBV 感染通过调节与细胞凋亡相关的基因，导致胃癌对 5-FU 的耐药性。
