Department of Medical Microbiology, School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China.
Department of Medical Microbiology, School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China; Shandong College of Traditional Chinese Medicine, 508 Binhai East Road, Yantai, 264199, China.
Virus Res. 2021 Feb;293:198253. doi: 10.1016/j.virusres.2020.198253. Epub 2020 Dec 10.
Epstein-Barr virus (EBV)-associated gastric carcinoma (GC) comprises approximately 9% of all cases of GC. EBV-associated GC (EBVaGC) has characteristic clinicopathological features for a favorable prognosis. Microtubule-associated protein 9 (MAP9) is a cell cycle-associated gene required for bipolar spindle assembly, mitosis progression, and cytokinesis. Nevertheless, to date, there have been no reports on MAP9 function in EBVaGC. In this study, we demonstrated that the mRNA and protein levels of MAP9 were up-regulated in EBV-positive gastric carcinoma cell lines. The positive rate of MAP9 expression in EBVaGC tissues was shown to be significantly higher than that in EBV-negative gastric carcinoma (EBVnGC) tissues. Additionally, the expression of MAP9 was partly increased in EBVnGC cell lines by interfering with DNA methyltransferase 1 (DNMT1) or treated with 5-aza-2'-deoxycytidine. Thus, EBV may regulate MAP9 expression by modifying the methylation of MAP9 CpG islands through DNMT1. By inhibiting the expression of MAP9 with small interfere sequence in the EBV-positive GC cell line GT38 and overexpressing MAP9 in the EBV-negative GC cell line AGS, we demonstrated that MAP9 inhibited the growth and induced apoptosis of EBVaGC cells significantly. In conclusion, our study demonstrated that EBV can up-regulate the expression of MAP9 in EBVaGC, and the methylation of MAP9 CpG islands influences this regulation. And MAP9 acts as a tumor suppressor in the development of EBVaGC.
EB 病毒（EBV）相关胃癌（GC）约占所有 GC 的 9%。EBV 相关胃癌（EBVaGC）具有特征性的临床病理特征，预后良好。微管相关蛋白 9（MAP9）是细胞周期相关基因，对于双极纺锤体组装、有丝分裂进展和胞质分裂是必需的。然而，迄今为止，尚未有关于 MAP9 在 EBVaGC 中的功能的报道。在这项研究中，我们证明了 MAP9 的 mRNA 和蛋白水平在 EBV 阳性胃癌细胞系中上调。MAP9 表达在 EBVaGC 组织中的阳性率明显高于 EBV 阴性胃癌（EBVnGC）组织。此外，通过干扰 DNA 甲基转移酶 1（DNMT1）或用 5-氮杂-2'-脱氧胞苷处理，EBVnGC 细胞系中的 MAP9 表达部分增加。因此，EBV 可能通过修饰 DNMT1 来调节 MAP9 启动子 CpG 岛的甲基化，从而调节 MAP9 的表达。通过在 EBV 阳性 GC 细胞系 GT38 中用小干扰序列抑制 MAP9 的表达，以及在 EBV 阴性 GC 细胞系 AGS 中过表达 MAP9，我们证明 MAP9 显著抑制 EBVaGC 细胞的生长并诱导其凋亡。总之，我们的研究表明，EBV 可以上调 EBVaGC 中 MAP9 的表达，而 MAP9 CpG 岛的甲基化影响这种调节。并且 MAP9 在 EBVaGC 的发生发展中起抑癌作用。
