Project 4-Oncomodulatory role of HCMV in glial tumors

项目4-HCMV在神经胶质瘤中的肿瘤调节作用

• 批准号: 9209613
• 负责人: DONNA M NEUMANN
• 金额: $ 21.9万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9209613
• 关键词: Accounting; Adult; Alpha Cell; Apoptosis; Biopsy; Brain Neoplasms; Catalytic Domain; Cell Cycle Regulation; Cell Differentiation process; Cells; Chromatin; Chronic; Clinical; Clonal Expansion; Complex; Coupled; Cytomegalovirus; Cytomegalovirus Infections; DNA; DNA sequencing; Data; Detection; Development; Diagnosis; Drug resistance; EZH2 gene; Early Promoters; Environment; Epigenetic Process; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Glioblastoma; Glioma; Goals; Growth; Human; Immediate-Early Genes; Immune Evasion; Immunohistochemistry; In Situ Hybridization; Incidence; Infection; Investigation; Lead; Link; Lytic Phase; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Neoplasm Metastasis; Nucleic Acids; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Phosphorylation; Polycomb; Primary Brain Neoplasms; Property; Proteins; RNA; Radiation; Recurrence; Reporting; Research; Resistance; Risk; Role; STAT3 gene; Sampling; Solid Neoplasm; Specimen; Testing; Therapeutic Intervention; Time; Tumorigenicity; Viral; Virus; Western Blotting; Xenograft procedure; angiogenesis; chemotherapy; gene product; gene repression; in vivo; interest; novel; oncology; outcome forecast; overexpression; temozolomide; therapeutic evaluation; tumor; tumor progression; tumorigenic; viral DNA

Abstract: Gliomas are the most commonly diagnosed primary brain tumors, accounting for approximately 45-50% of all primary brain tumors. Glioblastoma multiforme (GBM) is the most aggressive of the primary brain cancers and despite advancements in surgery, radiation and chemotherapy, remains incurable. Further, human cytomegalovirus (hCMV) has been implicated in the development and progression of human glioblastomas through unknown mechanisms. The presence and role of hCMV infection in glioblastomas and GBM has remained a controversial topic over the last decade. Nonetheless, several groups have demonstrated the presence of CMV nucleic acids and proteins in primary and recurrent GBM specimens using immunohistochemistry (IHC), RNA and DNA in situ hybridization (ISH), qualitative and quantitative real-time PCR coupled with viral DNA sequencing, and western blot (WB) analysis. Subsequent research, including our preliminary studies, has also demonstrated that several hCMV gene products that have oncomodulatory properties are expressed in GBM and may be impacting tumor pathogenesis in vivo by modulating GBM proliferation, apoptosis, angiogenesis, invasion and immune evasion. Because HCMV is a ubiquitous human virus that infects 50-90% of adults in the US, investigation of its potential oncomodulatory role in glioblastomas, particularly the aggressive GBM, is highly relevant. We hypothesize that persistent HCMV infections lead to a dysregulation of the cellular epigenetic environment that results in the overexpression of EZH2 and activation of the STAT3 pathway to enhance tumor pathogenesis in glioblastoma. To test this hypothesis, we will: 1) Determine whether HCMV persistence enhances tumor pathogenesis in glioblastoma cells through the dysregulation of epigenetic pathways involved in cell cycle control and differentiation. 2) Establish the role of HCMV persistence in tumor progression and glioblastoma drug resistance in intracranial xenografts. 3) Determine whether overexpression of EZH2 correlates with incidence of HCMV infection in glioblastoma biopsies. The long-term goal is to identify novel pathways regulated through HCMV persistent infection that could lead to glioblastoma tumor progression and CNS invasion. The results of this research are expected to provide the framework for future studies testing therapeutic interventions, which maintain the normal epigenetic state of a cell and decrease the risk of CMV-associated tumor progression.

摘要：胶质瘤是最常见的原发脑肿瘤，占 约占所有原发性脑肿瘤的45%-50%。多形性胶质母细胞瘤(GBM)是最常见的 原发脑癌的侵袭性，尽管外科手术、放射治疗和 化疗，仍然是无法治愈的。此外，人类巨细胞病毒(HCMV)与 人脑胶质母细胞瘤的发生和发展机制不明。这个 人巨细胞病毒感染在胶质母细胞瘤和胶质母细胞瘤中的存在及其作用一直是一个有争议的话题 在过去的十年里。尽管如此，有几个小组已经证明了CMV核的存在 免疫组织化学(IHC)、核糖核酸在原发和复发基底膜标本中的酸和蛋白质 以及DNA原位杂交(ISH)、定性和定量实时聚合酶链式反应与病毒DNA的结合 测序和蛋白质印迹(WB)分析。后续的研究，包括我们的初步研究， 也证明了几种具有肿瘤调节特性的HCMV基因产物是 在基底膜中表达，并可能通过调节基底膜而影响体内肿瘤的发病 增殖、凋亡、血管生成、侵袭和免疫逃避。因为巨细胞病毒是一种无处不在的 感染美国50%-90%成年人的人类病毒，研究其潜在的肿瘤调节作用 在胶质母细胞瘤中，尤其是侵袭性的基底膜，是高度相关的。我们假设，坚持不懈 巨细胞病毒感染导致细胞表观遗传环境的失调，从而导致 EZH2的过表达和STAT3通路的激活促进肿瘤的发生 胶质母细胞瘤。为了验证这一假设，我们将：1)确定HCMV持久性是否增强 胶质母细胞瘤细胞中表观遗传途径失调的肿瘤发病机制 在细胞周期控制和分化方面。2)确定人巨细胞病毒持久性在肿瘤中的作用 颅内异种移植瘤的进展及耐药情况。3)确定是否 在胶质母细胞瘤活检组织中，EZH2的过度表达与巨细胞病毒感染的发生率相关。 长期目标是确定通过hcmv持续感染调节的新途径。 这可能导致胶质母细胞瘤的肿瘤进展和中枢神经系统的侵袭。这项研究的结果是 预计将为未来测试治疗干预措施的研究提供框架，这些研究保持 细胞的正常表观遗传状态，并降低巨细胞病毒相关肿瘤进展的风险。