IL10 and IGF1 Receptor Axis in Prostate Cancer

描述：（从申请人的摘要扫描）IGF-R1轴似乎 在调节基质金属蛋白酶-2的产生中起主要作用， 前列腺癌的发生我们的初步数据表明IL- 10 阻断IGF- 1诱导的人前列腺肿瘤细胞MMP-2的合成 (i.e.用端粒酶基因永生化的HPCA-10 c细胞）。我们已经发现 IL- 10通过一种新的“LIM结构域”信号蛋白（33 Kda）触发信号传导 其结合MM-P-2的沉默元件（p53增强子位点的上游 启动子阻断IGF-1（和p53）诱导的转录。两个假设将是 在本授权申请中测试的，即：（1）IL-10：IL-10受体 轴下调MMP-2的产生（通过激活一个新的33 Kda（Sif） 转录调节蛋白，其结合转录因子的抑制元件（Si）。 （2）IL-10转染阻断IGF-1：IGF-受体 1轴诱导MMP-2的表达。IL-10实验将 确定IL-10转染对IGF-1 R轴和MMP-2的影响 在两种原代人前列腺癌细胞系（即雄激素 依赖性HPCA-10a细胞和雄激素非依赖性HPCA-10 c系） 通过转染端粒酶基因使其永生化。HPCA-i 0a的性能 和10 c细胞（即IL-10转染的细胞）将在原位杂交中进行比较。 在生长、血管生成和转移方面， 行为;加上小鼠存活率。基因表达谱相关的 IGF-R1和IL-10 R轴（即Sif和MMP-2）将通过北方 印迹和免疫学技术。最后，这些基因的表达 (and相关基因）将在档案（~ 150/年）人前列腺中进行检查 腺体（即良性、HGPIN、癌症）精囊和局部转移， 整个封片切片免疫标记。总的来说，这些研究应该确定 IL-10 R和/或IGF-R1轴是否在前列腺肿瘤生长中起作用， 转移靶向IL-10 R或IL-10 R受体的治疗剂的开发 IGF-R1轴在治疗本病中应是有益的。

DESCRIPTION: (Scanned from the applicant's abstract) The IGF-Rl axis appears to play a major role in regulating matrix metalloproteinase-2 production and the tumorigenesis of prostate cancer. Our preliminary data indicate that IL- 10 blocks IGF- 1 induced MMP-2 synthesis in primary human prostate tumor lines (i.e. HPCA-10c cells immortalized with the telomerase gene). We have discovered that IL- 10 triggers signaling by a novel 'LIM domain' signal protein (33 Kda) which binds a silencer element (upstream of a p53 enhancer site) of the MM-P-2 promoter to block IGF-1 (and p53) induced transcription. Two hypotheses will be tested in this grant application, namely that: (1) the IL-10:IL-l0 receptor axis down regulates MMP-2 production (via activation of a novel 33 Kda (S if) transcription regulatory protein that binds a suppressor element (Si) of the MMP-2- 5' promoter; and that (2) IL-10 transfection blocks IGF-i :IGF-receptor 1 axis induction of MMP-2 expression in vitro. The IL-10 experiments will determine the influence of IL-10 transfection on the IGF-1R axis and MMP-2 expression in two primary human prostate cancer cell lines (i.e. androgen dependent HPCA-10a cells and androgen independent HPCA- 1 Oc lines) immortalized by transfection with the telomerase gene. The behavior of HPCA-i0a and lOc cells (i.e. IL-lO transfected cells) will be compared in an orthotopic tumor model in SCID mice in terms of growth, angiogenesis and metastatic behavior; plus mouse survival rates. Gene expression profiles related to the IGF-R1 and IL-10R axis (i.e. Sif and MMP-2) will be assessed by Northern blotting and immunological techniques. Finally, the expression of these genes (and related genes) will be examined in archival (-150/yr) human prostate glands (i.e. benign, HGPIN, cancer) seminal vesicle and localized metastases by immunolabeling of whole mount sections. Overall, the studies should determine whether the IL-i OR and/or IGF-R1 axis play a role in prostate tumor growth and metastasis. Development of therapeutic agents, which target the IL-10R or IGF-R1 axis should be beneficial in the treatment of the disease.