Project 3-Human papillomavirus in HIV associated lung cancers

项目3-人类乳头瘤病毒在HIV相关肺癌中的作用

• 批准号: 10223350
• 负责人: Zhen Lin
• 金额: $ 28万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223350
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Cancer cell line; Cell Culture Techniques; Cells; Clinical; Copy Number Polymorphism; DNA; Data; Data Set; Detection; Disease Management; Environment; Epithelial Cells; Estrogen Receptor alpha; Etiology; Evaluation; Future; Gene Mutation; General Population; Genes; Genetic Transcription; Genomic DNA; Genomics; Goals; Growth; HIV; HPV-High Risk; Highly Active Antiretroviral Therapy; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Incidence; Individual; Induced Mutation; Infection; Informatics; Lung; Lung Neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mutation; Nucleotides; Odds Ratio; Oncogenic; Oncology; Pathogenesis; Pathway interactions; Patient Care; Patients; Phenotype; Population; Reporting; Research; Rest; Risk Factors; Role; Sampling; Signal Transduction; Smoking; Smoking Status; Solid; Testing; Therapeutic; Time; Tissues; Transcript; Tumor Tissue; Variant; Viral; Viral Oncogene; Virus Integration; Work; base; cancer risk; driver mutation; established cell line; fusion gene; gene product; genome sequencing; human papilloma virus oncogene; improved; in vivo; infection rate; insertion/deletion mutation; insight; knock-down; lung cancer cell; lung carcinogenesis; mortality; power analysis; transcriptome; transcriptome sequencing; tumor; tumorigenesis; virome; whole genome

Abstract: In recent years, AIDS-related mortality has dramatically decreased due to the highly active antiretroviral therapy (HAART) but the mortality caused by the non-AIDS-defining cancers, especially lung cancer (LC) is continuously rising. In the U.S., LC becomes the most common and most deadly non-AIDS- defining cancer in HIV(+) populations. Although smoking is a key risk factor for HIV associated LCs, HIV(+) individuals still have a significantly increased LC risk after controlling for smoking status, indicating that other factors are responsible for the higher LC incidence in HIV(+) populations. Existing etiology studies have been largely focused on the involvement of human papillomavirus (HPV) in non-HIV associated LCs. A study to investigate the role of HPV in HIV associated LCs has not yet been reported. To date, the view on whether or not HPV is associated with LCs is highly controversial, since the observed HPV infection rate in LCs varies from 0 to 100%. Further, the hypothetic role of HPV in LCs is mainly based on the detection of HPV genomic DNA in LCs. So far, none of the association studies has demonstrated that the detected HPV DNA is transcriptionally active in the lung tumor tissues. Without evidence of viral transcription, the causal role of HPV in LCs is highly questionable, since it's well known that HPV must be transcriptionally active in order to induce its associated cancers. The overarching goal of this proposal is to resolve this long-standing controversy of the involvement of HPV in LCs using our cutting-edge sequencing and informatics approaches and information obtained from the natural in vivo tumor environment. To accomplish this goal, we will first examine our hypothesis that HPV is causally associated with a subset of LCs in HIV(+) population, but not in the general population. The rest of the work will test our hypothesis that HPV promotes lung oncogenesis by inducing a unique set of cancer driver mutations and manipulating cancer pathways through synergistic expression of viral E5 and E7 genes. By conducting the proposed work, we expect to get solid evidence supporting a causal role of HPV in HIV associated LCs and obtain much needed, unprecedented insight into the unique mechanism underlying the HPV(+) LCs in HIV infected individuals, which may be particularly significant for future patient care and disease management.

摘要：近年来，由于艾滋病的高度活跃， 抗逆转录病毒治疗（HAART），但非艾滋病定义的癌症，特别是肺癌， 癌症（LC）的发病率在不断上升。在美国，LC成为最常见和最致命的非艾滋病- HIV（+）人群中的癌症定义。虽然吸烟是HIV相关LC的一个关键风险因素，但HIV（+） 在控制吸烟状态后，个体仍然具有显著增加的LC风险，表明其他 因素是导致HIV（+）人群中LC发病率较高的原因。现有的病因学研究已经 主要集中在非HIV相关LC中人乳头瘤病毒（HPV）的参与。一项研究以 研究HPV在HIV相关LC中的作用尚未报道。到目前为止，关于是否或 由于观察到的LC中HPV感染率不同，因此HPV与LC无关是高度有争议的 从0到100%。此外，HPV在LC中的假设作用主要基于HPV基因组的检测。 LC中的DNA。到目前为止，还没有相关研究证明检测到的HPV DNA是 在肺肿瘤组织中具有转录活性。在没有病毒转录证据的情况下，HPV的因果作用 在LC中的作用是非常值得怀疑的，因为众所周知，HPV必须是转录活性的，以诱导 与之相关的癌症该提案的总体目标是解决这一长期存在的争议， 利用我们先进的测序和信息学方法和信息， 从天然的体内肿瘤环境中获得。为了实现这一目标，我们将首先检查我们的 假设HPV与HIV（+）人群中的LC子集存在因果关系，但在一般人群中不存在 人口其余的工作将验证我们的假设，即HPV通过诱导肺内的肿瘤细胞增殖来促进肺癌的发生。 一组独特的癌症驱动突变，并通过协同表达病毒 E5和E7基因。通过开展拟议的工作，我们期望得到支持因果作用的确凿证据 在HIV相关的LC中检测HPV，并获得对独特机制的急需的，前所未有的见解 在HIV感染者中，HPV（+）LC是潜在的，这对未来的患者可能特别重要。 护理和疾病管理。