Comprehensive analyses of Epstein-Barr virus(EBV) -dependent cellular gene expressions responsible for the viral oncogenesis

全面分析负责病毒肿瘤发生的 Epstein-Barr 病毒 (EBV) 依赖性细胞基因表达

• 批准号: 17590418
• 负责人: IMAI Shosuke
• 金额: $ 2.3万
• 依托单位: Kochi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590418/
• 关键词: Epstein-Barr virus(EBV); oncogenic genes; microarray; T; NK cell tumor; epithelial tumor; cytokines; 上皮細胞; NK細胞

The aim of this study was to identify the cellular genes closely related to or responsible for Epstein-Barr virus (EBV)-induced oncogenesis in naturally EBV-positive T/NK and epithelial tumor cells, by utilizing a unique molecule capable of eradicating EBV episomes from cells, i.e., dominant-negative EBNA1 (DNE1; Mol. Ther., 11(4):578-90, 2005). We prepared isogenic pairs of EBV-positive and-negative cell lines by DNE1 transduction and compared their malignant grade. Concomitantly alterations of cellular gene expression in those cell pairs were comprehensively assessed with the multi-cytokine assay and GeneChip microarray system, thereby elucidating the role(s) of EBV in malignant conversion. The results obtained are as follows.1. Adenovirus vector-mediated transduction of our DNE1 successfully eradicated EBV episomes from the majority of naturally EBV-positive T/NK lymphoma and epithelial tumor cell lines in a few days.2. The EBV-lost T/NK cells produced by DNE1 showed a striking suppression of their malignant phenotypes, such as prolongation of doubling time and loss of anchorage-independent growth potential, compared with parental EBV-harboring T/NK tumor cells. In a part of the EBV-lost T/NK cells, loss of viral genome also brought about cell death.3. The EBV-lost T/NK cells showed significantly decreased production of some cytokines, such as interleukin-9, compared with the parental EBV-harboring T/NK tumor cells. Conversely, the production levels of a few other cytokines were also found to be upregulated in the EBV-lost T/NK cells.These results indicate that the EBV-dependent malignant phenotypes in T/NK cells and perhaps also in epithelial cells, as in B-cell malignancy, are associated at least partly with upregulation (i.e., the autocrine mechanism) and/or downregulation of certain cytokine genes. We are planning to explore precisely the mechanisms of cytokine gene control and specific effects on EBV oncogenesis.

本研究的目的是通过利用能够从细胞中根除EBV附加体的独特分子，即，显性阴性EBNA 1（DNE 1; Mol.治疗：11（4）：578-90，2005）。我们通过DNE 1转导制备了EBV阳性和阴性细胞系的同基因对，并比较了它们的恶性程度。同时用多细胞因子测定和基因芯片系统全面评估这些细胞对中细胞基因表达的改变，从而阐明EBV在恶性转化中的作用。研究结果如下：1.腺病毒载体介导的DNE 1转导在几天内成功地从大多数自然EBV阳性的T/NK淋巴瘤和上皮肿瘤细胞系中根除EBV附加体.与亲代携带EBV的T/NK肿瘤细胞相比，DNE 1产生的EBV缺失的T/NK细胞显示出对其恶性表型的显著抑制，例如倍增时间延长和锚定非依赖性生长潜力的丧失。在部分EBV失活的T/NK细胞中，病毒基因组的缺失也导致细胞死亡.与亲代携带EBV的T/NK肿瘤细胞相比，EBV丢失的T/NK细胞显示出一些细胞因子如白细胞介素-9的产生显著降低。这些结果表明，T/NK细胞中的EBV依赖性恶性表型以及可能还有上皮细胞中的EBV依赖性恶性表型，如B细胞恶性肿瘤中的EBV依赖性恶性表型，至少部分与EBV依赖性恶性表型的上调相关（即，自分泌机制）和/或某些细胞因子基因的下调。我们正计划探索细胞因子基因控制的机制和对EBV肿瘤发生的特异性影响。

项目成果

A functional polymorphism in MMP-9 is associated with childhood atopic asthma

• DOI: 10.1016/j.bbrc.2006.03.102
• 发表时间: 2006-05-26
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Nakashima, K;Hirota, T;Tamari, M
• 通讯作者: Tamari, M

Proposed guidelines for diagnosing chronic active Epstein-Barr virus infection

• DOI: 10.1002/ajh.20398
• 发表时间: 2005-09-01
• 期刊: AMERICAN JOURNAL OF HEMATOLOGY
• 影响因子: 12.8
• 作者: Okano, M;Kawa, K;Imashuku, S
• 通讯作者: Imashuku, S

H. pylori感染以外の胃癌の成因 (3) EBウイルスと胃癌

H. pylori感染以外的胃癌原因（三）EB病毒与胃癌

• 发表时间: 2006
• 期刊: 臨床消化器内科 21(8)
• 作者: 脇口 宏;前田明彦;堂野純孝;他;脇口 宏;脇口 宏;Kamakura M;Daibata M;Uehara Y;Fukushima A;今井章介;今井章介
• 通讯作者: 今井章介

バクテリオファージ療法

噬菌体疗法

• 发表时间: 2006
• 期刊: 医学のあゆみ 219(6)
• 作者: Morishima S;Akatsuka Y;Nawa A;Kondo E;Kiyono T;Torikai H;Nakanishi T;Ito Y;Tsujimura K;Iwata K;Ito K;Kodera Y;Morishima Y;Kuzushima K;Takahashi T;Ito Y;内山淳平
• 通讯作者: 内山淳平

Microarray as astandard laboratory technique

微阵列作为标准实验室技术

• 发表时间: 2005
• 期刊: Allergolohy Int 3
• 作者: Isomura;H.;Stinski;M.F.;Kudoh;A.;Daikoku;T.;Shirata;N.;Tsurumi;Saito H
• 通讯作者: Saito H