Androgen and Soluble Guanylyl Cyclase Signaling in Prostate Cancer

描述（申请人提供）：前列腺癌的生长和进展依赖于雄激素和AR（雄激素受体）。AR在前列腺中的主要功能是调节前列腺细胞的增殖和存活，并且该功能由AR调节基因表达的能力介导。虽然许多雄激素调节基因已被确定在前列腺中，很少有已被证明在前列腺癌细胞的生长和进展中发挥关键作用。这使我们假设尚未鉴定的基因产物可能在介导AR对细胞增殖的影响中很重要。通过对LNCaP细胞的基因阵列研究，我们确定sGC 11是一个新的雄激素调节基因，其表达水平与前列腺癌细胞增殖直接相关。这是基于我们实验室的几个关键观察结果。首先，sGC 11的siRNA敲除严重损害了雄激素依赖性和非依赖性LNCaP细胞的增殖。其次，sGC 11在雄激素非依赖性细胞中的表达是高的，并且雄激素无反应。最后，sGC 11在雄激素依赖性细胞中的过表达足以再现其雄激素诱导的生长。此外，使用前列腺组织的初步表达数据显示，sGC 11在恶性雄激素依赖性前列腺癌中高度表达，并且在晚期雄激素非依赖性前列腺癌中显著升高。我们的总体假设是sGC 11是前列腺癌发生中AR作用的重要组成部分。因此，本提案的具体目的是（1）研究sGC 11在前列腺癌细胞的增殖、凋亡和肿瘤发生中的作用，（2）阐明负责sGC 11在前列腺癌细胞中的促增殖作用的信号通路，（3）研究雄激素调节前列腺癌细胞中sGC 11表达的机制，（4）检测前列腺癌进展过程中sGC 11的表达。鉴于AR在前列腺癌发生发展中的重要性，sGC 11作为一个新的雄激素调节基因的鉴定可能为研究雄激素和AR在前列腺癌发生中的作用提供重要工具。由于sGC 11在前列腺癌细胞增殖中的作用和最近发现的抗p53活性，sGC 11可能在前列腺癌的发生和发展中非常重要，因此是未来癌症治疗的潜在靶点。公共卫生相关性：前列腺癌是男性死亡的第二大原因，正在经历从可治疗的依赖性前列腺癌到通常致命的难治性前列腺癌的转变。雄激素受体和调节因子是前列腺癌两个阶段的关键因素。我们已经确定了sGC 11作为一种新的雄激素调节基因的重要性，雄激素依赖性和更重要的是，雄激素非依赖性前列腺癌细胞的增殖，我们建议在这里研究sGC 11在前列腺癌细胞的生长和肿瘤发生中的作用。

DESCRIPTION (provided by applicant): The growth and progression of prostate cancer are dependent on androgens and AR (androgen receptor). The major function of AR in the prostate is to regulate the proliferation and survival of prostate cells and this function is mediated by the ability of AR to modulate gene expression. While many androgen-regulated genes have been identified in the prostate, few have been shown to play a pivotal role in prostate cancer cell growth and progression. This led us to postulate that gene products not yet identified may be important in mediating the AR effects on cellular proliferation. Through gene array studies in LNCaP cells, we identified sGC11 as a novel androgen-regulated gene, whose expression level is directly related to prostate cancer cell proliferation. We base this on several key observations from our laboratory. First, siRNA knock-down of sGC11 severely compromised the proliferation of both androgen-dependent and -independent LNCaP cells. Secondly, sGC11 expression in androgen-independent cells is high and androgen unresponsive. Finally, sGC11 over- expression in androgen-dependent cells is sufficient for reproducing their androgen-induced growth. In addition, preliminary expression data using prostate tissues show that sGC11 is highly expressed in malignant androgen-dependent prostate cancer, and this is significantly elevated beyond this in advanced androgen- independent prostate cancer. Our overall hypothesis is that sGC11 is an important component of AR action in prostate carcinogenesis. Accordingly, the specific aims of this proposal are to (1) study the role of sGC11 in the proliferation, apoptosis, and tumorigenesis of prostate cancer cells, (2) elucidate the signaling pathway that is responsible for pro-proliferative actions of sGC11 in prostate cancer cells, (3) study the mechanism of androgen regulation of sGC11 expression in prostate cancer cells, and (4) measure the expression of sGC11 during the progression of prostate cancer. In view of the importance of AR in the development and progression of prostate cancer, the identification of sGC11 as a novel androgen-regulated gene may provide an important tool for studying the role of androgens and AR in prostate carcinogenesis. Because of its implicated role in the proliferation of prostate cancer cells and recently identified anti-p53 activity, sGC11 may be very important in the initiation and progression of prostate cancer and thus be a potential target of future cancer therapies. PUBLIC HEALTH RELEVANCE: Prostate cancer is the second leading cause of death among men, undergoing a transition from the treatable hormone-dependent to the usually lethal hormone-refractory. The androgen receptor and regulatory factors are key factors in both stages of prostate cancer. We have identified sGC11 as a novel androgen-regulated gene important for the proliferation of both androgen-dependent and, more importantly, androgen-independent prostate cancer cells, and we propose here study the role of sGC11 in the growth and tumorigenesis of prostate cancer cells.