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

人前列腺癌的生长和转移需要血管生成。白细胞介素（IL）-8是一种在晚期前列腺癌中过度表达的促血管生成因子。IL-8在前列腺癌中的表达是如何调节的尚不清楚。转化生长因子（TGF）-β 1也在晚期前列腺癌中过表达，通过未知机制促进血管生成。Dong博士先前的研究表明，干扰素β基因治疗下调TGF-β 1和IL-8的表达，抑制血管生成，并抑制小鼠中人前列腺癌细胞原位肿瘤的生长。他的初步研究表明，前列腺癌细胞组成性表达TGF-β 1和IL-8，TGF-β 1增强IL-8的表达。他假设TGF-β 1是肿瘤环境中刺激人前列腺癌中IL-8表达的主要因素。他将检验这一假设，并研究TGF-β 1刺激IL-8在人前列腺癌细胞、裸鼠前列腺癌原位模型和人前列腺癌手术标本中表达的机制。在具体目标1中，他将进一步描述TGF-β 1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-β 1下调、TGF-β 1及其受体相互作用中断以及TGF-β受体恢复对IL-8表达的影响。在具体目标2中，他将研究TGF-β 1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。将测定由具有不同转移潜能的细胞或由用TGF-β信号传导途径中三种关键分子的显性负突变体稳定转染的细胞形成的肿瘤中IL-8和TGF-β 1的表达。具体目标3将确定TGF-β 1过表达与IL-8表达、血管生成和肿瘤转移的相关性。 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-β 1调节IL-8表达的分子途径。将测定缺乏三种TGF-β信号传导途径以及相关转录因子的细胞中TGF-β 1刺激的IL-8表达和IL-8基因启动子激活。

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.