Regulation of Invasion and Metastasis by HIF-1 Oral Squamous Cell Carcinoma

描述(申请人提供)：项目摘要：抗药性一直是口腔鳞状细胞癌(OSCC)的一个令人烦恼的挑战。在肿瘤微环境中，口腔鳞状细胞癌细胞迅速消耗局部血管供应的氧气和营养物质。虽然低氧可能抑制新的细胞分裂或增加细胞死亡，但那些最能适应低氧和低血糖的细胞可能具有选择性优势，导致恶性行为增加。事实上，研究已经证明了肿瘤缺氧与增强对放射治疗和化疗的抵抗力之间的关系。缺氧诱导因子-1(HIF-1)是一种异源二聚体转录因子，在氧稳态调节中起重要作用。HIF-1α亚基的表达和活性受细胞内氧浓度以及多种生长因子和信号通路的影响。目前已鉴定出70多个HIF-1靶基因，它们对血管生成、糖酵解和其他适应机制至关重要。口咽部肿瘤中HIF-1表达增加与患者预后不良相关。本研究旨在探讨HIF-1在口腔鳞癌侵袭转移中的作用。在特定的目标1中，我们将阐明HIF-1在口腔鳞癌侵袭和转移中的作用。我们将表征HIF-1在调控口腔鳞状细胞癌侵袭和转移候选基因中的作用。了解HIF-1在口腔鳞癌中调控改变的生化和分子基础可以为限制口腔鳞癌侵袭和转移和改善患者生存提供新的治疗干预措施。 应聘者是一名头颈肿瘤外科医生，具有信号转导和头颈癌方面的研究背景。他的职业目标是将了解口腔鳞癌转移和侵袭的进展转化为头颈癌患者的新的有效治疗干预措施。他的机构致力于实现这一目标，并提供了必要的空间、受保护的时间和资源。他已经组建了一支导师和顾问团队，他们不仅将提供广泛的科学指导，还将促进他作为一名独立调查人员的发展。 相关性：头颈癌的发病率和死亡率通常与肿瘤通过局部侵袭和远处转移而扩散有关。了解HIF-1在口腔鳞癌侵袭和转移中的作用，可能为诊断生物标记物和旨在监测和预防肿瘤扩散的治疗方法的开发确定新的靶点。这些研究将直接使头颈癌患者受益，并可能为其他类型癌症中肿瘤扩散的调节提供有价值的见解。

DESCRIPTION (provided by applicant): Project Summary: Resistance to treatment has been a vexing challenge for oral squamous cell carcinoma (OSCC). Within the tumor microenvironment, OSCC cells rapidly expend oxygen and nutrients supplied by the local vasculature. Although hypoxia may inhibit new cell division or increase cell death, those cells most capable of adapting to hypoxia and hypoglycemia may have a selective advantage leading to increased malignant behavior. Indeed, studies have demonstrated a relationship between tumor hypoxia and increased resistance to radiation therapy and chemotherapy. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor that plays an essential role in regulating oxygen homeostasis. Expression and activity of the HIF-1 a subunit is influenced by cellular oxygen concentration, as well as numerous growth factors and signaling pathways. Over 70 HIF-1 target genes have been identified that are crucial for angiogenesis, glycolysis and other adaptive mechanisms. Increased HIF-1 expression within oropharyngeal tumors is correlated with worse patient prognosis. This research project is focused upon the role of HIF-1 in modulating OSCC invasion and metastasis. In Specific Aim 1, we will elucidate the function of HIF-1 in OSCC invasion and metastasis. We will characterize the contribution of HIF-1 to the regulation of candidate genes that mediate invasion and metastasis in OSCC in Specific Aim 2. Understanding the biochemical and molecular basis for the altered regulation of HIF-1 in OSCC could lead to opportunities for new therapeutic interventions to limit OSCC invasion and metastasis and improve patient survival. The candidate is a head and neck oncologic surgeon with a research background in signal transduction and head and neck cancer. His career goal is to translate advances in the understanding of OSCC metastasis and invasion into novel and effective therapeutic interventions for head and neck cancer patients. His institution is committed to this goal and has provided the necessary space, protected time and resources. He has assembled a team of mentors and consultants who will not only provide extensive scientific guidance, but also foster his development as an independent investigator. Relevance: Morbidity and mortality due to head and neck cancers is often related to tumor spread by local invasion and distant metastasis. Understanding the role of HIF-1 in OSCC invasion and metastasis may identify new targets for the development of diagnostic biomarkers and therapies designed to monitor and prevent tumor spread. These studies will directly benefit patients with head and neck cancer and may provide valuable insight into the regulation of tumor spread in other types of cancer.