Nuclear Neuropilin2: a novel molecular mediator for aggressive Prostate Cancer

摘要 局限性前列腺癌通常被归类为惰性或侵袭性，这主要是基于 临床和病理特点。尽管我们对基因改变的理解是 前列腺癌(Pca)的不同分期尚无明确的分子分类 该系统可以预测发生侵袭性前列腺癌的风险。因此，它目前是 在早期阶段很难区分好斗和懒惰的PCA，并发展 侵袭性癌症患者的适当治疗。手术、放疗和较少使用 雄激素剥夺疗法是局部肿瘤的有效治疗选择，尽管 30%-35%的患者癌症复发，其中一些人演变为转移性疾病。确实有 晚期前列腺癌的治疗选择非常有限。因此，重要的是确定 促进前列腺癌进展的分子介质。全面了解 这些介体的功能不仅有助于我们确定可以 区分侵袭性和惰性PCa，还要建立有效的治疗模式 适用于那些高风险患转移性癌症的患者。我们的初步结果 提示Neuropilin-2(NRP2)可能是侵袭性前列腺癌的中介物。 癌症促进所需基因的转录。从机制上讲，NRP2可以从 内质网逆行转运至核膜并稳定转录机制 是癌症促进基因表达所必需的。基于这些新奇的观察，我们 假设核NRP2对于转录所需基因是关键的 主成分分析的进展。因此，NRP2不仅是侵袭性前列腺癌的预测因子，也是靶点。 寻求有效的治疗策略。提出了两个具体目标。在目标1中，我们将研究 核膜结合的NRP2如何与细胞相互作用的潜在机制 Pca细胞中的转录因子，并促进其活性。我们还将使用队列来确定 人前列腺癌组织中核NRP2是否可以作为预后因子，从而可以区分 在懒惰和咄咄逼人的PCA之间。目标2将侧重于分子机制如何 NRP2迁移到核膜上，并确定抑制这种转位是否可以 阻断前列腺癌的生长。总而言之，我们的提案将决定核反应堆2如何 可促进PCA，因此可作为进攻性PCA的有效预测指标。此外，它还将确定 靶向NRP2轴，如阻断其核转运是否有效 治疗侵袭性前列腺癌的方法。

Abstract Localized prostate cancer is often categorized as either indolent or aggressive based largely on clinical and pathological features. Despite our understanding of genetic alterations that are associated with different stages of prostate cancer (PCa), there is no clear molecular classification system, which can predict the risk for developing aggressive PCa. As a result, it is currently difficult to discriminate the aggressive and indolent PCa in their early stages, and develop appropriate therapy for the patients with aggressive cancer. Surgery, radiation and less often androgen deprivation therapies are the available treatment options for localized tumor, although cancers of 30-35% of patients recur and some of them evolve into metastatic disease. There are very limited treatment options for advanced stage PCa. It is therefore important to identify the molecular mediators that promote the advancement of PCa. A comprehensive knowledge on the function of these mediators will not only help us to determine the molecular factors that can distinguish the aggressive and indolent PCa but also to establish effective treatment modalities for those patients who are at high risk to develop metastatic cancer. Our preliminary results indicated that Neuropilin-2 (NRP2) could be a mediator of aggressive PCa by regulating the global transcription of genes required for cancer promotion. Mechanistically, NRP2 can translocate from ER to nuclear membrane through retrograde transport and stabilize the transcription machineries necessary for the expression of cancer promoting genes. Based on these novel observations, we hypothesized that nuclear NRP2 is critical for the transcription of genes required for the advancement of PCa. Hence, NRP2 is not only a predictor for aggressive PCa but also a target for effective treatment strategy. Two specific aims have been proposed. In aim 1, we will study the underlying mechanisms of how nuclear membrane-bound NRP2 interacts with the transcription factors in PCa cells and facilitates their activity. We will also determine using a cohort of human PCa tissues whether nuclear NRP2 can be a prognostic factor, which can discriminate between indolent and aggressive PCa. Aim 2 will focus on the molecular mechanism of how NRP2 migrates to nuclear membrane and determine whether inhibition of this translocation can block the prostate tumor growth. Altogether, our proposal will determine how nuclear NRP2 promotes PCa and thus can be an effective predictor for aggressive PCa. Moreover, it will identify whether targeting NRP2 axis such as blocking its nuclear transport is an effective therapeutic approach to treat aggressive PCa.