2023 Fiscal Year Final Research Report

Importance of cell differentiation and lytic viral replication in EBV-related epithelial tumor formation

Research Project

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Project/Area Number	21K07054
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 49060:Virology-related
Research Institution	Shimane University
Principal Investigator	Yoshiyama Hironori 島根大学, 学術研究院医学・看護学系, 教授 (10253147)
Co-Investigator(Kenkyū-buntansha)	小野村大地島根大学, 学術研究院医学・看護学系, 特任助教 (00910697)
Project Period (FY)	2021-04-01 – 2024-03-31
Keywords	Epstein-Barr virus / 上皮性腫瘍 / 細胞分化 / メチル化 / ヒットエンドラン仮説
Outline of Final Research Achievements	It was hypothesized that higher cell differentiation levels lead to lytic EBV infection, increasing cellular motility and promoting tumorigenesis. The adhesion of H. pylori to gastric epithelial cells induced the expression of low-affinity EBV receptors, enhancing EBV infection efficiency and contributing to EBV-associated gastric cancer development. Transcriptome analysis revealed that the IL6/JAK/STAT3 and TNF-α/NF-κB signaling pathways are characteristics of EBV-associated epithelial cancers. Moreover, SLC26A9 and TMC8 were identified as distinctive genes predictive of prognosis in EBV-associated epithelial cancers. Additionally, EBV infection induced the Warburg effect and cancer stemness, contributing to the progression of EBV-positive oral squamous cell carcinoma. Finally, the demethylating agent MC180295 was shown to inhibit DNA repair and cell cycle progression, thereby suppressing the proliferation of EBV-associated gastric cancer cells.
Free Research Field	ウイルス学
Academic Significance and Societal Importance of the Research Achievements	EBVの感染はWarburg効果および癌幹細胞性を誘導し、EBV関連上皮性腫瘍の進行に重要であると考えられた。分化状態で発現する細胞遺伝子がEBV関連上皮癌の予後を予測できる特徴的な遺伝子として考えられた。EBV感染の痕跡がある胃癌症例では、Timp2およびEya1遺伝子のメチル化が、EBVの痕跡がない症例よりも、高いレベルで認められた。脱メチル化剤のMC180295はDNA修復と細胞周期を抑制し、EBVaGC細胞の増殖を阻害した。これらの結果から、EBVのウイルス遺伝子発現を調節する上皮細胞内環境を詳細にすることで、EBV関連上皮性腫瘍に特異的な治療法が開発できると考えられる。