Prostaglandin D and skin cancer prevention

前列腺素 D 与皮肤癌预防

• 批准号: 7502019
• 负责人: HENRY J LIN
• 金额: $ 6.57万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7502019
• 关键词: Anabolism; Blood; Blood Circulation; Chemicals; Chemoprevention; Chemopreventive Agent; Coupled; Data; Development; Dinoprostone; Enzymes; Flushing; GTP-Binding Proteins; Goals; Hand; Hematopoietic; Intestines; Knock-out; Knockout Mice; Langerhans cell; Lead; Malignant Neoplasms; Modeling; Mus; Nicotinic Acids; Organ; Pathway interactions; Production; Prostaglandin D2; Prostaglandin E Receptor; Prostaglandins; Prostaglandins D; Protein Overexpression; Publishing; Range; Research Personnel; Role; Route; Skin; Skin Cancer; Skin Neoplasms; TP53 gene; Transgenes; Transgenic Organisms; Translating; UV induced; United States; Work; adenoma; angiogenesis; cancer chemoprevention; cell growth; improved; insight; macrophage; monocyte; mouse model; prostaglandin R2 D-isomerase; receptor; research study; skin cancer prevention; tumor; tumor growth; tumorigenic; ultraviolet irradiation

DESCRIPTION (provided by applicant): Skin cancer is the most common cancer in the United States, with over 1,300,000 new cases per year. The overall goals are to understand how prostaglandin pathways influence development of skin tumors and use the information to improve cancer chemoprevention. The prostaglandin cascade makes prostaglandins E2, D2 (PGE2, PGD2), and other prostanoids. PGD2 promotes tumors in the skin and other organs. For bowel tumors, experiments showed that adenoma-prone ApcMin/+ mice had 50% more tumors when deficient in hematopoietic prostaglandin D synthase (H-PGDS). Conversely, mice had 70% fewer tumors, if they had a transgene causing high levels of H-PGDS. Thus, PGD2 production appears to suppress tumors. Niacin dramatically raises blood levels of PGD2 (causing flushing). The rise in PGD2 is due to the G-protein- coupled nicotinic acid receptor, which stimulates the prostaglandin cascade in Langerhans cells in the skin. Thus, the hypotheses are: (i) PGD2 production may suppress skin tumors, similar to the effect observed for bowel tumors and (ii) niacin may be a chemopreventive agent, due to niacin-responsive Langerhans cells in skin. The proposed experiments will manipulate PGD2 production and assess effects on a mouse model of skin cancer. Specific Aims are: (1) Define effects of H-PGDS transgenes and H-PGDS knockouts on UV-induced skin tumors in heterozygous p53 knockout mice; (2) define effects of dietary niacin on UV-induced skin tumors in heterozygous p53 knockout mice. Significance: Results should give new insight into roles and mechanisms of prostaglandins in tumor growth. Niacin as a booster of PGD2 may emerge as an agent to be studied for chemoprevention of skin cancer.

描述(由申请人提供)： 皮肤癌是美国最常见的癌症，每年有超过130万新病例。总体目标是了解前列腺素途径如何影响皮肤肿瘤的发展，并利用这些信息来改善癌症的化学预防。前列腺素级联反应产生前列腺素E2、D2(PGE2、PGD2)和其他前列腺素。PGD2促进皮肤和其他器官的肿瘤。对于肠道肿瘤，实验表明，当缺乏造血前列腺素D合成酶(H-PGDS)时，易患腺瘤的ApcMin/+小鼠的肿瘤发生率增加50%。相反，如果小鼠携带了导致高水平H-PGDS的转基因，那么它们的肿瘤发病率就会减少70%。因此，PGD2的产生似乎可以抑制肿瘤。烟酸极大地提高了血液中PGD2的水平(导致脸红)。PGD2的升高是由于G蛋白偶联的烟酸受体，它刺激皮肤朗格汉斯细胞中的前列腺素级联。因此，假设：(I)PGD2的产生可以抑制皮肤肿瘤，类似于对肠道肿瘤所观察到的效果；(Ii)由于皮肤中对烟酸有反应的朗格汉斯细胞，烟酸可能是一种化学预防药物。拟议的实验将操纵PGD2的产生，并评估对皮肤癌小鼠模型的影响。具体目的是：(1)明确H-PGDS转基因和H-PGDS敲除对杂合子p53基因敲除小鼠紫外线诱导皮肤肿瘤的影响；(2)确定饮食烟酸对杂合子p53基因敲除小鼠紫外线诱导皮肤肿瘤的影响。意义：研究结果将为前列腺素在肿瘤生长中的作用和机制提供新的见解。烟酸作为PGD2的促进剂可能成为皮肤癌化学预防的研究对象。