Estrogen reduces HPV transcription and oncogene expression to target disease

雌激素可降低 HPV 转录和癌基因表达以靶向疾病

• 批准号: 10201571
• 负责人: Molly L Bristol
• 金额: $ 14.75万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201571
• 关键词: Affect; Antiviral Agents; Area; Attenuated; Base Pairing; Binding; Blood; Bypass; Cancer Burden; Cancer Cell Growth; Cancer Etiology; Carcinogens; Cell Line; Cell Survival; Cells; Clinic; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Cytostatics; Data; Disease; Dose; Epidemic; Epithelial Cells; Estrogen Receptor alpha; Estrogen Therapy; Estrogens; Funding; Future; Gene Expression; Genetic Enhancer Element; Genetic Transcription; Goals; Grant; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Hela Cells; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papillomavirus 16; Human papillomavirus 18; In Vitro; Incidence; Individual; Infection; Investigation; Knowledge; Lead; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mediating; Mucous Membrane; Mus; Mutagenesis; Nucleic Acid Regulatory Sequences; Oncogenes; Outcome; Postmenopause; Preventive vaccine; Publishing; Radiation; Radiation therapy; Reporting; Repression; Research; Retinoblastoma Protein; Risk; Sex Differences; Sexually Transmitted Diseases; Skin; Smoking; TP53 gene; Testing; Therapeutic; Translating; Tumor Suppressor Proteins; Viral; Viral Genes; Viral Load result; Viral Oncogene; Virus; Virus Replication; Vision; Woman; Work; Xenograft Model; attenuation; cancer cell; cancer therapy; carcinogenesis; cell growth; cell killing; cytotoxic; estrogenic; high risk; improved; in vivo; male; malignant oropharynx neoplasm; men; middle age; new therapeutic target; novel; prevent; radiation response; receptor; response; sexually active; treatment strategy; tumor

Project Summary / Abstract Human papillomaviruses (HPVs) are the most common sexually transmitted infection that affects nearly every sexually active individual at some point in their lives. A portion of these infections can result in cancer, and worldwide, as many as 5% of cancers are caused by this virus. There has been an increase in HPV-related head and neck cancer, and recently HPV has bypassed smoking as the main cause of this disease. The HPV vaccine protects against future infections but will not help anyone who already has HPV. As there are no treatments for this virus, this is a much needed area of research. Promising targets for anti-HPV therapeutics include viral replication and transcription. Here we present evidence that estrogen reduces HPV transcription through interactions with the viral long control region (LCR). Novel regulatory regions have also been discovered in the LCR that result in the loss of transcription. Reduced LCR transcription via estrogen translates to a reduction in early viral genes, including the oncogene E6. Lower levels of E6 allow for re-expression of the cellular tumor suppressor p53 and preliminary evidence suggests that this provides an HPV-specific loss in cell viability. The proposal seeks to expand upon these results to determine if the estrogenic effects are cytostatic or cytotoxic, and determine if these effects can be translated into an in vivo xenograft model. Data generated from these studies will generate the necessary data for a future R01 application to investigate the novel LCR regulatory regions, and possible sex related differences in the response to estrogen treatment to elucidate why the incidence of HPV-associated HNSCC is found at 3 fold higher levels in men than women, a currently understudied area. The ultimate goals of this proposal and future studies generated from this data is to limit viral load, cure infections, prevent downstream carcinogenesis, discover HPV-targeted cancer treatments, and to translate these approaches to the clinic.

项目总结/摘要 人乳头瘤病毒（HPV）是最常见的性传播感染 几乎影响到每一个性活跃的个体在他们生命中的某个时刻。一部分这些 感染可能导致癌症，在世界范围内，多达5%的癌症是由这种感染引起的。 病毒与HPV相关的头颈癌有所增加，最近HPV已经 吸烟是导致这种疾病的主要原因。HPV疫苗可以预防未来 感染，但不会帮助任何人谁已经有HPV。因为没有治疗方法 病毒，这是一个非常需要研究的领域。抗HPV治疗的有希望的靶点 包括病毒复制和转录。在这里，我们提出的证据表明，雌激素减少HPV 通过与病毒长控制区（LCR）的相互作用进行转录。新调节 在LCR中也发现了导致转录损失的区域。减少 通过雌激素的LCR转录转化为早期病毒基因的减少，包括 癌基因E6。较低水平的E6允许细胞肿瘤抑制因子p53的重新表达 初步证据表明，这提供了细胞活力的HPV特异性损失。的 一项提案试图扩大这些结果，以确定雌激素效应是否是细胞抑制性的 或细胞毒性，并确定这些作用是否可以转化为体内异种移植模型。 这些研究产生的数据将为未来的R 01应用程序生成必要的数据 研究新的LCR调控区，以及在这些基因中可能存在的性别相关差异。 雌激素治疗的反应，以阐明为什么HPV相关HNSCC的发病率是 在男性中发现的水平比女性高3倍，这是目前研究不足的领域。最终 该提案的目标和从该数据产生的未来研究是限制病毒载量，治愈 感染，预防下游致癌作用，发现HPV靶向癌症治疗方法， 将这些方法应用于临床。