Ferroportin Repression in Head and Neck Squamous Cell Carcinoma

头颈鳞状细胞癌中的铁转运蛋白抑制

• 批准号: 10358548
• 负责人: Benjamin Ross Belvin
• 金额: $ 7.7万
• 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: 2020-03-25 至 2023-03-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358548
• 关键词: Binding; Binding Sites; Biochemical; Biology; Cancer Biology; Cancer cell line; Cell Death; Cell Line; Cell Proliferation; Cells; Cellular biology; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Disseminated Malignant Neoplasm; Distant; Elements; Endocytosis Induction; Environment; Enzyme-Linked Immunosorbent Assay; Experimental Models; Fellowship; Fibroblasts; Gases; Gingiva; Goals; Growth; Head Cancer; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Homeostasis; Homologous Gene; Hormones; Human; Iron; Life; Light; Lymphoma; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Membrane; Membrane Proteins; Mentors; Migration Assay; Modeling; Molecular; Mouth Diseases; Neoplasm Metastasis; Normal Cell; Oral; Oral cavity; Oral health; Organism; Outcome; Oxidation-Reduction; Pharmaceutical Preparations; Physiology; Plasma; Play; Predisposition; Primary Neoplasm; Process; Production; Property; Proteins; Proteolysis; Reaction; Recombinants; Regulation; Repression; Roentgen Rays; Role; Structural Models; Structure; System; Testing; Training; Work; Xenograft Model; cancer type; cell type; experience; hepcidin; keratinocyte; knock-down; malignant breast neoplasm; malignant mouth neoplasm; metal transporting protein 1; migration; new therapeutic target; novel; novel therapeutic intervention; small hairpin RNA; therapeutic evaluation; therapeutic target; tumor; tumor progression

Project Summary Iron is an essential element that is required in nearly all living organisms. Due to its gas binding and redox properties it plays an irreplaceable role in human physiology helping to facilitate the reactions necessary to sustain life. Ferroportin (FPN) acts as the sole iron efflux protein in humans, and all iron transport to the plasma occurs through this single channel. Thus, FPN plays a critical role in the maintenance of human iron homeostasis. The regulatory hormone hepcidin controls the levels of membrane associated FPN through the induction of endocytosis and proteasomal degradation via direct binding. Despite its importance to host physiology, very little is known about the role FPN, and iron homeostasis, plays in progression of head and neck cancers. Preliminary work shows that FPN is expressed in normal cells of the oral cavity (oral keratinocytes and gingival fibroblasts). We show repression of FPN and de-regulation of iron homeostasis occurs in advanced (metastatic) head and neck squamous cell carcinoma (HNSCC). Preliminary data also reveals that cell lines with reduced ferroportin levels may make cells more sensitive to ferroptosis. Immunoblots reveal the expression of hepcidin in HNSCC cell lines, indicating that aberrant hepcidin expression may play a role in ferroportin repression in these cell types. The goal of this proposal is to investigate the role FPN repression plays in the progression of HNSCC. We will also probe the interaction of FPN and hepcidin through Small Angle X-ray scattering (SAXS) to shed light on the molecular mechanisms of hepcidin mediated repression of FPN. In aim 1 we will investigate the clinicopathology of FPN repression in HNSCC. We will modulate ferroportin levels in HNSCC cell lines and observe the effect it has on cell proliferation, metastatic potential, and sensitivity to ferroptosis. In aim 2 we will we will explore the role hepcidin plays in the repression of FPN and investigate the allosteric mechanisms of the hepcidin-FPN interaction using SAXS. The findings in this study, despite the outcomes, will be important in characterizing the role iron homeostasis plays in oral health and disease. This fellowship training plan will provide the applicant experience in the fields of cell and cancer biology as well as in the handling and purification of membrane proteins. Training of the applicant will be sponsored by mentors with expertise in the fields of iron biology and cancer biology, as well as in an environment with other trainees.

项目摘要 铁是几乎所有活生物体所需的重要元素。由于其气体结合和氧化还原 它在人类生理学中起不可替代的作用，有助于促进对反应的作用 维持生命。亚铁蛋白（FPN）充当人类的唯一铁外排蛋白，所有铁运输到等离子体 通过此单个通道发生。因此，FPN在维持人铁稳态中起着至关重要的作用。 调节激素肝素通过诱导控制膜相关FPN的水平 内吞作用和蛋白酶体降解通过直接结合。尽管对托管生理学的重要性很重要，但很少 关于FPN和铁稳态的角色，在头部和颈部癌症的进展中都知道。初步的 工作表明，FPN在口腔正常细胞（口腔角质形成细胞和牙龈成纤维细胞）中表达。 我们显示了对FPN的抑制和铁稳态的负调控，发生在高级（转移）头部，并且 颈部鳞状细胞癌（HNSCC）。初步数据还表明，铁蛋白减少的细胞系 水平可能会使细胞对铁铁作用更敏感。免疫印迹揭示了肝素在HNSCC中的表达 细胞系，表明异常的肝素表达可能在这些细胞类型中的铁蛋白抑制中起作用。 该提案的目的是研究FPN抑制在HNSCC发展中的作用。我们将 还可以通过小角度X射线散射（SAX）探测FPN和肝素的相互作用 肝素介导的FPN抑制的分子机制。在AIM 1中，我们将研究临床病理学 HNSCC中的FPN抑制作用。我们将调节HNSCC细胞系中的铁蛋白水平，并观察它的效果 具有细胞增殖，转移性潜力和对铁凋亡的敏感性。在目标2中，我们将探索 Hepcidin在FPN的抑制中发挥作用并研究肝素FPN的变构机制 使用SAXS交互。尽管结果取得了结果，但本研究的发现对于表征 角色铁稳态在口腔健康和疾病中发挥作用。该奖学金培训计划将为申请人提供 在细胞和癌症生物学领域以及膜的处理和纯化方面的经验 蛋白质。申请人的培训将由具有铁生物学领域专业知识的导师赞助 癌症生物学以及与其他学员的环境中。