Effect of oxidative stress response in HPV16 mediated oropharyngeal carcinogenesis

氧化应激反应在HPV16介导的口咽癌发生中的作用

• 批准号: 530794353
• 负责人: Professor Dr. Baki Akgül, Ph.D.
• 金额: --
• 依托单位: Jean-Uhrmacher-Institut für klinische HNO-Forschung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/530794353?language=en
• 关键词: Effect; oxidative; stress; response; HPV16

Human papillomavirus (HPV) is a pivotal risk factor for the development of oropharyngeal squamous cell carcinoma (OPSCC), with an increasing incidence reported in several countries. With a prevalence of more than 80%, high-risk HPV16 is the most common type detected in OPSCC. We recently showed that in both HPV16-positive and HPV-negative OPSCC, there is a subgroup characterized by oxidative/metabolic stress-related signatures and upregulation of aldo-keto-reductases, AKR1C1 and AKR1C3, going along with unfavourable prognosis. Upregulation of AKR1Cs prevents the accumulation of cytotoxic reactive oxygen species (ROS), an important mechanism leading to resistance against chemotherapeutic drugs such as cisplatin, which is used as a standard of care for OPSCC patients. The proposed grant application seeks to investigate the role of overexpressed AKR1Cs in HPV-induced OPSCC development. This study aims to understand the link between increased HPV16-E6*I expression, AKR1C1/C3 activation, and the associated metabolic reprogramming and oxidative stress in the context of malignant transformation. This grant covers the following two objectives: 1) To analyze the cell toxicity of a combination of AKR1C inhibitors and cisplatin on HPV-positive or -negative head and neck squamous cell carcinoma cell lines and on oral tumor development in HPV16 transgenic mice. 2) To determine the downstream effects of AKR1C1/C3 deregulation by HPV16 under oxidative stress on metabolic reprogramming. The aim of the study is to develop novel, de-escalating therapeutic approaches for HPV-induced tumours and thus define future treatment approaches for patients with favourable prognoses.

人乳头瘤病毒（HPV）是口咽鳞状细胞癌（OPSCC）发展的关键风险因素，在几个国家报告的发病率不断增加。高危型HPV 16的患病率超过80%，是OPSCC中最常见的类型。我们最近发现，在HPV 16阳性和HPV阴性的OPSCC中，有一个亚组的特征是氧化/代谢应激相关的特征和醛酮还原酶AKR 1C 1和AKR 1C 3的上调，沿着预后不良。AKR 1C的上调可防止细胞毒性活性氧（ROS）的积累，这是导致对化疗药物（如顺铂）耐药性的重要机制，顺铂被用作OPSCC患者的标准治疗。拟议的拨款申请旨在研究过表达的AKR 1C在HPV诱导的OPSCC发展中的作用。本研究旨在了解在恶性转化的背景下，HPV 16-E6*I表达增加，AKR 1C 1/C3激活以及相关的代谢重编程和氧化应激之间的联系。该资助包括以下两个目标：1）分析AKR 1C抑制剂和顺铂组合对HPV阳性或阴性头颈部鳞状细胞癌细胞系和HPV 16转基因小鼠口腔肿瘤发展的细胞毒性。2)确定在氧化应激条件下HPV 16引起的AKR 1C 1/C3失调对代谢重编程的下游影响。该研究的目的是为HPV诱导的肿瘤开发新的、逐步降低的治疗方法，从而为具有有利肿瘤的患者确定未来的治疗方法。