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

前列腺癌的生长和转移需要血管生成。白细胞介素8(IL-8)是一种在晚期前列腺癌中高表达的促血管生成因子。目前尚不清楚前列腺癌中IL-8的表达是如何调节的。转化生长因子-β1在晚期前列腺癌中也过表达，其促进血管生成的机制尚不清楚。董博士之前的研究表明，干扰素-β基因治疗下调了转化生长因子-β1和IL-8的表达，抑制了血管生成，并抑制了小鼠前列腺癌原位肿瘤的生长。他的初步研究表明，前列腺癌细胞结构性地表达转化生长因子-β1和白介素8，转化生长因子-β1促进白介素8的表达。他假设转化生长因子-β1是肿瘤环境中刺激人类前列腺癌IL-8表达的主要因素。他将验证这一假说，并研究转化生长因子-β1刺激人前列腺癌细胞、裸鼠前列腺癌原位模型和人类前列腺癌手术标本中IL-8表达的机制。在具体目标1中，他将进一步表征转化生长因子-β1在刺激前列腺癌细胞IL-8表达中的作用。内源性转化生长因子-β1的下调、转化生长因子-β1及其受体相互作用的阻断和转化生长因子-β受体的恢复对IL-8表达的影响将被确定。在具体目标2中，他将研究转化生长因子-β1和转化生长因子-β信号通路在调节人前列腺癌裸鼠原位肿瘤中IL-8表达的作用。检测具有不同转移潜能的细胞和稳定转导转化生长因子-β信号通路中三个关键分子的显性负突变体形成的肿瘤组织中IL-8和转化生长因子-β1的表达。特异性目标3将确定转化生长因子-β1的过度表达与IL-8表达、血管生成和转移的相关性 人前列腺癌的手术标本。在具体目标4中，他将研究通过转化生长因子-β1调节IL-8表达的分子途径。在缺乏三条转化生长因子-β信号通路的细胞中，转化生长因子-β1刺激的IL-8的表达和IL-8基因启动子的激活以及涉及的转录因子将被确定。

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.