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: 10133449
• 负责人: Benjamin Ross Belvin
• 金额: $ 7.35万
• 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/10133449
• 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.

项目概要 铁是几乎所有生物体所需的必需元素。由于其气体结合和氧化还原作用 它在人体生理学中发挥着不可替代的作用，有助于促进必要的反应 维持生命。铁转运蛋白 (FPN) 是人体中唯一的铁流出蛋白，所有铁均转运至血浆 通过这个单一渠道发生。因此，FPN 在维持人体铁稳态中起着至关重要的作用。 调节激素铁调素通过诱导 FPN 来控制膜相关 FPN 的水平 通过直接结合进行内吞作用和蛋白酶体降解。尽管它对宿主生理学很重要，但很少 FPN 和铁稳态在头颈癌进展中的作用众所周知。初步的 研究表明，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。 我们发现 FPN 受到抑制，铁稳态失调发生在晚期（转移性）头部和 颈部鳞状细胞癌（HNSCC）。初步数据还表明，铁转运蛋白减少的细胞系 水平可能会使细胞对铁死亡更加敏感。免疫印迹揭示 HNSCC 中铁调素的表达 细胞系，表明异常的铁调素表达可能在这些细胞类型中铁转运蛋白抑制中发挥作用。 该提案的目的是研究 FPN 抑制在 HNSCC 进展中的作用。我们将 还通过小角 X 射线散射 (SAXS) 探测 FPN 和铁调素的相互作用，以阐明 铁调素介导的 FPN 抑制的分子机制。在目标 1 中，我们将研究临床病理学 HNSCC 中的 FPN 抑制。我们将调节 HNSCC 细胞系中的铁转运蛋白水平并观察其效果 对细胞增殖、转移潜能和对铁死亡的敏感性具有影响。在目标 2 中，我们将探索 Hepcidin 在抑制 FPN 中的作用并研究 Hepcidin-FPN 的变构机制 使用 SAXS 进行交互。尽管有这样的结果，这项研究的结果对于表征 铁稳态在口腔健康和疾病中的作用。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处理和纯化方面拥有丰富的经验 蛋白质。申请人的培训将由具有铁生物学和铁生物学领域专业知识的导师赞助 癌症生物学，以及与其他学员一起的环境。