TGF-beta 1-regulated IL-8 expression in prostate cancer

TGF-β1 调节前列腺癌中 IL-8 的表达

• 批准号: 6613210
• 负责人: Zhongyun Dong
• 金额: $ 26.88万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613210
• 关键词: angiogenesis; angiogenesis factor; athymic mouse; clinical research; densitometry; enzyme linked immunosorbent assay; gel mobility shift assay; gene expression; gene induction /repression; histopathology; human tissue; immunocytochemistry; in situ hybridization; interleukin 8; metastasis; northern blottings; nuclear runoff assay; pathologic process; prostate neoplasms; receptor expression; statistics /biometry; transcription factor; transforming growth factors

Growth and metastasis of human prostate cancer require angiogenesis. Interleukin (IL)-8 is a proangiogenic factor overexpressed in advanced human prostate cancer. How IL-8 expression is regulated in prostate cancer is unclear. Transforming growth factor (TGF)-beta 1, also overexpressed in advanced prostate cancer, promotes angiogenesis by unknown mechanisms. Dr. Dong's previous studies show that interferon-beta gene therapy down regulates TGF-beta1 and IL-8 expression, inhibits angiogenesis, and suppresses growth of orthotopic tumors of human prostate cancer cells in mice. His preliminary studies show that prostate cancer cells constitutively express TGF-beta1 and IL-8, and TGF-beta 1 enhances IL-8 expression. He hypothesizes that TGF-beta1 is the primary factor in tumor environment that stimulates IL-8 expression in human prostate cancer. He will test this hypothesis and investigate mechanisms by which TGF-beta1 stimulates IL-8 expression in human prostate cancer cells, in orthotopic models of prostate cancer in nude mice, and in surgical specimens of human prostate cancers. In specific aim 1, he will further characterize the role of TGF-beta1 in stimulating IL-8 expression in prostate cancer cells. Effects of downregulation of endogenous TGF-beta1, interruption of TGF-beta1 and its receptor interaction, and restoration of TGF-beta receptor on IL-8 expression will be determined. In specific aim 2, he will study the role of TGF-beta1 and TGF-beta signaling pathways in regulating IL-8 expression in orthotopic tumors of human prostate cancer cells in nude mice. Expression of IL-8 and TGF-beta1 in tumors formed by cells with different metastatic potentials or by those stablely transfected with dominant negative mutants of three key molecules in TGF-beta signaling pathways will be determined. Specific aim 3 will determine the correlation of TGF-beta1 overexpression with IL-8 expression, angiogenesis, and metastasis in surgical specimens of human prostate cancers. In specific aim 4, he will investigate molecular pathways that regulate IL-8 expression by TGF-beta1. TGF-beta1-stimulated IL-8 expression and IL-8 gene promoter activation in cells lacking the three TGF-beta signaling pathways as well as transcription factors involved will be determined.

人类前列腺癌的生长和转移需要血管生成。白细胞介素 (IL)-8 是一种在晚期人类前列腺癌中过度表达的促血管生成因子。 IL-8 表达在前列腺癌中的调节机制尚不清楚。转化生长因子 (TGF)-β 1 在晚期前列腺癌中也过度表达，通过未知机制促进血管生成。董博士之前的研究表明，干扰素-β基因疗法可下调TGF-β1和IL-8的表达，抑制血管生成，并抑制小鼠体内人类前列腺癌细胞原位肿瘤的生长。他的初步研究表明，前列腺癌细胞组成型表达TGF-β1和IL-8，并且TGF-β1增强IL-8的表达。他假设 TGF-β1 是肿瘤环境中刺激人类前列腺癌中 IL-8 表达的主要因素。他将测试这一假设，并研究 TGF-β1 在人类前列腺癌细胞、裸鼠前列腺癌原位模型以及人类前列腺癌手术标本中刺激 IL-8 表达的机制。在具体目标 1 中，他将进一步表征 TGF-β1 在刺激前列腺癌细胞中 IL-8 表达中的作用。将确定内源性TGF-β1的下调、TGF-β1及其受体相互作用的中断以及TGF-β受体的恢复对IL-8表达的影响。在具体目标2中，他将研究TGF-β1和TGF-β信号通路在调节裸鼠人前列腺癌细胞原位肿瘤中IL-8表达中的作用。将测定具有不同转移潜能的细胞或稳定转染 TGF-β 信号通路中三个关键分子的显性失活突变体的细胞形成的肿瘤中 IL-8 和 TGF-β1 的表达。具体目标 3 将确定 TGF-β1 过表达与 IL-8 表达、血管生成和转移的相关性 人类前列腺癌的手术标本。在具体目标 4 中，他将研究通过 TGF-β1 调节 IL-8 表达的分子途径。将确定缺乏三个 TGF-β 信号通路以及相关转录因子的细胞中 TGF-β1 刺激的 IL-8 表达和 IL-8 基因启动子激活。