IL10 and IGF1 Receptor Axis in Prostate Cancer

描述：(从申请人的摘要中扫描)IGF-RL轴似乎 在调节基质金属蛋白酶-2的产生中起主要作用 前列腺癌的肿瘤发生。我们的初步数据显示，IL-10 阻断胰岛素样生长因子-1诱导的人前列腺癌原代细胞基质金属蛋白酶-2的合成 (即携带端粒酶基因永生化的HPCA-10c细胞)。我们发现 IL-10通过一种新的LIM结构域信号蛋白(33kda)触发信号 它结合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。将有两个假设 在这项拨款申请中测试的，即：(1)IL-10：IL-10受体 轴向下调节基质金属蛋白酶-2的产生(通过激活一个新的33KDA(S IF)) 转录调节蛋白，与抑制元件(Si)结合 MMP2-5‘启动子；(2)IL-10转染阻断IGF-I：IGF-受体 1轴体外诱导基质金属蛋白酶-2的表达。IL-10实验将 IL-10基因转染对胰岛素样生长因子-1R轴和基质金属蛋白酶-2的影响 两种原代人前列腺癌细胞系(即雄激素)的表达 依赖的HPCA-10a细胞和雄激素非依赖的HPCA-1 Oc系) 通过导入端粒酶基因而永垂不朽。HPCA-10a的行为 和LoC细胞(即IL-LO转基因细胞)将在原位进行比较 SCID小鼠肿瘤模型的生长、血管生成和转移 行为；加上老鼠的存活率。与基因表达谱相关的 IGF-R1和IL-10R轴(即Sif和MMP-2)将由Northern进行评估 印迹和免疫学技术。最后，这些基因的表达 (和相关基因)将在人类前列腺档案(-150/年)中进行检查 腺体(即良性、HGPIN、癌症)、精囊和局部转移 对整个安装节进行免疫标记。总体而言，这些研究应该确定 IL-I OR和/或IGF-R1轴是否在前列腺癌的生长和发展中起作用 转移。以IL-10R为靶点的治疗剂的开发 IGF-R1轴在本病的治疗中可能是有益的。

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.