CYTOKINE REGULATION OF ANGIOGENESIS IN OVARIAN CANCER

卵巢癌血管生成的细胞因子调节

• 批准号: 7610052
• 负责人: KAREN M LOUNSBURY
• 金额: $ 1.32万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610052
• 关键词: Cell Survival; Cells; Computer Retrieval of Information on Scientific Projects Database; Energy Metabolism; Erythropoiesis; Funding; Genetic Transcription; Grant; Human; Immune system; Immunohistochemistry; Institution; Interleukin-6; Literature; Malignant neoplasm of ovary; Modeling; Operative Surgical Procedures; Pathway interactions; Play; Proteins; Regulation; Research; Research Personnel; Resources; Role; Source; Specimen; United States National Institutes of Health; Vascular Endothelial Growth Factors; angiogenesis; autocrine; cytokine; transcription factor; tumor; tumor growth

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The HIF-1¿ transcription factor plays a vital role in the transcription of genes related to erythropoiesis, energy metabolism, angiogenesis and cell survival. Studies show that HIF-1¿ expression increases as the ovarian cancer advances and its expression can be regulated by cytokines. Cytokines help in tumor growth by increasing tumor proliferation and angiogenesis and by inhibiting the immune system. IL-6 and TNF-¿ are significantly highly expressed in human ovarian cancer specimens. Literature states that TNF-¿ increases IL-6 secretion and also stabilizes HIF-1¿ protein. According to our cytokine model we propose that TNF-¿ increases IL-6 secretion and later IL-6 acts on the cell in an autocrine fashion and through PI3-K pathway causes stabilization of HIF-1¿ protein. HIF-1¿ further leads to transcription of VEGF which stimulates angiogenesis. To prove this we blocked NF¿B with classical IKK blocker, Bay-11 in varying concentrations, hypothesizing to inhibit TNF-¿ activity and thus destabilizing HIF-1¿ in the presence of 10ng/ml of TNF-¿. We observed that Bay-11 increased HIF-1¿ stabilization in the presence of TNF-¿. We also performed immunohistochemistry on human surgical ovarian cancer specimens for HIF-1¿, VEGF, IL-6 and PECAM. In the presence of high HIF-1¿, there were high levels of VEGF, and IL-6 but during low HIF-1¿, VEGF and IL-6 expressions were variable. We conclude that TNF-¿ stabilizes HIF-1¿ but the role of NF¿B is uncertain and that there exists a correlation between high HIF-1¿, VEGF and IL-6 in ovarian cancer.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 HIF-1€转录因子在与促红细胞生成，能量代谢，血管生成和细胞存活相关的基因转录中起着至关重要的作用。研究表明，随着卵巢癌的进展，HIF-1表达会增加，其表达可以受细胞因子的调节。细胞因子通过增加肿瘤增殖和血管生成并抑制免疫系统来帮助肿瘤生长。 IL-6和TNF-在人卵巢癌标本中得到了高度表达。文献指出，TNF-增加了IL-6分泌并稳定HIF-1蛋白。根据我们的细胞因子模型，我们建议TNF-增加IL-6分泌，然后以自分泌方式和通过PI3-K途径在细胞上作用于细胞，从而导致HIF-1蛋白质稳定。 HIF-1。进一步导致VEGF的转录，刺激血管生成。为了证明这一点，我们用经典的IKK阻滞剂阻塞了NF¿B，bay-11的浓度不同，假设抑制TNF-oo的活性，从而在10ng/ml的TNF-®的情况下破坏了HIF-1。我们观察到，在TNF-€存在下，Bay-11增加了HIF-1？稳定。我们还针对HIF-1，VEGF，IL-6和PECAM进行了人类手术卵巢癌标本的免疫组织化学。在高HIF-1的存在下，有高水平的VEGF和IL-6，但是在低HIF-1中，VEGF和IL-6表达式是可变的。我们包括tnf-€稳定HIF-1。但是NF知识的作用尚不确定，并且在卵巢癌中存在高HIF-1，VEGF和IL-6之间存在相关性。