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：神经胶质瘤是最常见的原发性脑肿瘤，考虑到 大约45-50％的原发性脑肿瘤。胶质母细胞瘤多形（GBM）是最大的 主要脑癌的积极性，尽管手术，放射线和 化学疗法，仍然无法治愈。此外，人类巨细胞病毒（HCMV）已与 人类胶质母细胞瘤通过未知机制的发展和进展。这 HCMV感染在胶质母细胞瘤和GBM中的存在和作用仍然是一个有争议的话题 在过去的十年中。尽管如此，几组已经证明了CMV核的存在 使用免疫组织化学（IHC），RNA的原发性和复发性GBM标本中的酸和蛋白质 和原位杂交（ISH），定性和定量实时PCR与病毒DNA结合 测序和蛋白质印迹（WB）分析。随后的研究，包括我们的初步研究 还证明了具有启用调节特性的几种HCMV基因产物是 在GBM中表达，可能会通过调节GBM来影响体内肿瘤发病机理 增殖，凋亡，血管生成，侵袭和免疫逃避。因为HCMV无处不在 在美国感染50-90％的成年人的人类病毒，调查其潜在的调节作用 在胶质母细胞瘤中，尤其是侵略性GBM，非常相关。我们假设这一持久 HCMV感染导致细胞表观遗传环境的失调，导致 EZH2的过表达和STAT3途径的激活以增强肿瘤发病机理 胶质母细胞瘤。为了检验这一假设，我们将：1）确定HCMV持久性是否增强 胶质母细胞瘤细胞中的肿瘤发病机理通过涉及的表观遗传途径失调 在细胞周期控制和分化中。 2）确定HCMV持久性在肿瘤中的作用 颅内异种移植物中的进展和胶质母细胞瘤耐药性。 3）确定是否 EZH2的过表达与胶质母细胞瘤活检中HCMV感染的发生率相关。 长期目标是确定通过HCMV持续感染调节的新型途径 这可能导致胶质母细胞瘤肿瘤的进展和中枢神经系统侵袭。这项研究的结果是 预计将为未来的研究提供框架测试治疗干预措施，以维持 细胞的正常表观遗传状态，并降低了与CMV相关肿瘤进展的风险。