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，这一功能是由AR调节基因表达的能力所介导的。虽然已在前列腺中发现了许多雄激素调节基因，但很少有基因被证明在前列腺癌细胞的生长和发展中发挥关键作用。这导致我们假设，尚未确定的基因产物可能在调节AR对细胞增殖的影响方面发挥重要作用。通过对LNCaP细胞的基因芯片研究，我们发现sGC11是一个受雄激素调控的新基因，其表达水平与前列腺癌细胞的增殖密切相关。我们根据我们实验室的几个关键观察结果得出这一结论。首先，sGC11的siRNA敲除严重影响了雄激素依赖和非雄激素依赖的LNCaP细胞的增殖。其次，sGC11在雄激素非依赖性细胞中高表达，雄激素无反应。最后，sGC11在雄激素依赖的细胞中过表达足以复制雄激素诱导的生长。此外，使用前列腺组织的初步表达数据显示，sGC11在雄激素依赖的恶性前列腺癌中高表达，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，sGC11是前列腺癌发生过程中AR作用的重要组成部分。因此，本研究的具体目的是：(1)研究sGC11在前列腺癌细胞增殖、凋亡和肿瘤发生中的作用；(2)阐明sGC11促进前列腺癌细胞增殖的信号转导途径；(3)研究雄激素调节前列腺癌sGC11表达的机制；(4)检测sGC11在前列腺癌进展过程中的表达。鉴于AR在前列腺癌发生发展中的重要作用，发现sGC11是一个新的雄激素调节基因，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的工具。由于sGC11与前列腺癌细胞的增殖密切相关，并且最近被发现具有抗P53活性，因此它可能在前列腺癌的发生和发展中起着非常重要的作用，因此可能成为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激素依赖向通常致命的激素难治的转变。雄激素受体和调节因子是前列腺癌两个阶段的关键因素。我们发现sGC11是一个新的雄激素调控基因，对雄激素依赖性和更重要的雄激素非依赖性前列腺癌细胞的增殖都很重要，我们建议研究sGC11在前列腺癌细胞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.