Mechanisms of invasion for an HIV related head and neck cancer

HIV相关头颈癌的侵袭机制

基本信息

批准号：
8074500
负责人：
John H Lee
金额：
$ 35.27万
依托单位：
SANFORD RESEARCH/USD
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8074500
关键词：
Acquired Immunodeficiency Syndrome Affect Anchorage-Independent Growth Area Binding Binding Sites Biological Models Carcinoma Cause of Death Cells Clinical Data Development Diagnostic Epithelial Epithelial Cells Evaluation Event Goals Growth HIV HIV Infections Head and Neck Cancer Head and neck structure Human Human Papilloma Virus Vaccine Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 Immunoprecipitation In Vitro Incidence Knowledge Lesion Malignant - descriptor Malignant Neoplasms Malignant Squamous Cell Neoplasm Mediating Medical Methods Modeling Molecular Mus Oncogene Proteins Oncogenes Oncogenic Operative Surgical Procedures Pathway interactions Patients Phosphoric Monoester Hydrolases Play Point Mutation Process Protein Binding Protein Tyrosine Phosphatase Proteins Radiation Resistance Role Sampling Silent Mutation Telomerase Testing Therapeutic Tonsil Tonsillar Squamous Cell Carcinoma Treatment outcome Vaccines Work antiretroviral therapy base cancer cell cell growth cell transformation deletion analysis design epithelial to mesenchymal transition improved in vivo in vivo Model insight knock-down metaplastic cell transformation novel prevent prophylactic protein expression protein tyrosine phosphatase BL research study small hairpin RNA treatment strategy tumor growth ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): Head and neck squamous cell cancer (HNSCC) is a leading cause of death and disfigurement. A major limitation to improving treatment outcomes and survival has been a lack of understanding regarding cellular mechanisms involved in carcinogenic growth of relevant cells and thus a lack of mechanistically targeted therapies. Recent studies indicate that human papillomavirus (HPV) plays a major role in the development of HNSCC. Up to 60% of tonsillar SCC may be attributable to HPV infections. Compelling evidence indicates that HPV-related HNSCC is more common in patients with HIV, and recent studies suggest that antiretroviral therapies have no effect on reducing HPV-associated lesions. Despite the development of a prophylactic vaccine for HPV, there is no evidence that the vaccine would be effective at preventing HNSCC, particularly cancers associated with HIV infection. We have developed a unique in vitro and in vivo model system using human and mouse tonsillar epithelial cells to study progression to invasive malignancy. Our long-term goal is to understand key events of HPV-related tonsil epithelial cell transformation, and to use this information to develop molecular therapies that may be applicable to both HPV-positive and -negative HNSCC. We propose that HPV-mediated transformation and progression to malignancy depends on a novel HPV16 E6 oncoprotein function that is associated with its PDZ binding motif. We hypothesize that E6 mediated degradation of a PDZ containing tyrosine phosphatase, PTP-BL/FAP-1, is critical for an epithelial to mesenchymal transition (EMT) and anchorage independent growth (AIG), both key changes associated with the development of carcinomas. In these studies we will determine 1) what factors are required for malignant transformation of mouse and human tonsillar epithelial cells and whether loss of PTP-BL/FAP-1 is critical for this process, 2) how HPV E6 specifically degrades PTP-BL/FAP-1, and 3) the molecular mechanisms by which loss of PTP-BL/FAP-1 causes EMT and malignant progression. These studies will provide critical data for designing strategies to overcome EG-mediated transformation and may provide insight into treating non-HPV associated cancers. The knowledge gained from this work should make it possible to refine diagnostic and therapeutic methods for the treatment of HNSCC, an area of considerable unmet medical need, particularly in patients who suffer from complications associated with AIDS.

描述（由申请人提供）：头部和颈部鳞状细胞癌（HNSCC）是死亡和毁容的主要原因。改善治疗结果和生存的主要局限性是缺乏对相关细胞致癌生长的细胞机制的了解，因此缺乏机械靶向的疗法。最近的研究表明，人乳头瘤病毒（HPV）在HNSCC的发展中起着重要作用。多达60％的扁桃体SCC可能归因于HPV感染。令人信服的证据表明，与HPV相关的HNSCC在HIV患者中更为常见，最近的研究表明，抗逆转录病毒疗法对减少HPV相关病变没有影响。尽管开发了用于HPV的预防性疫苗，但没有证据表明该疫苗可以有效防止HNSCC，特别是与HIV感染相关的癌症。我们使用人和小鼠扁桃体上皮细胞开发了一种独特的体外和体内模型系统，以研究侵入性恶性肿瘤的发展。我们的长期目标是了解与HPV相关的扁桃体上皮细胞转化的关键事件，并使用这些信息来开发可能适用于HPV阳性和阴性HNSCC的分子疗法。我们建议HPV介导的转化和对恶性肿瘤的发展取决于与其PDZ结合基序相关的新型HPV16 E6癌蛋白功能。我们假设E6介导的含有酪氨酸磷酸酶PTP-BL/FAP-1的PDZ降解对于与癌瘤发展相关的间充质转变（EMT）和锚定独立生长（AIG）的上皮至关重要。 In these studies we will determine 1) what factors are required for malignant transformation of mouse and human tonsillar epithelial cells and whether loss of PTP-BL/FAP-1 is critical for this process, 2) how HPV E6 specifically degrades PTP-BL/FAP-1, and 3) the molecular mechanisms by which loss of PTP-BL/FAP-1 causes EMT and malignant progression.这些研究将为设计策略提供关键的数据来克服EG介导的转化，并可以洞悉治疗非HPV相关的癌症。从这项工作中获得的知识应该使您可以完善治疗HNSCC的诊断和治疗方法，而HNSCC是一个相当未满足的医疗需求的领域，尤其是在患有艾滋病并发症的患者中。