Nuclear Neuropilin2: a novel molecular mediator for aggressive Prostate Cancer

摘要 局限性前列腺癌通常被分类为惰性或侵袭性，主要基于 临床和病理特征。尽管我们了解基因改变， 与前列腺癌（PCa）的不同阶段相关，目前还没有明确的分子分类 该系统可以预测发展侵袭性PCa的风险。因此，目前 在早期阶段很难区分攻击性和惰性前列腺癌，并发展 为侵袭性癌症患者提供适当的治疗。手术，放疗， 雄激素剥夺疗法是局部肿瘤的可用治疗选择，尽管 30-35%的患者的癌症复发，并且其中一些发展成转移性疾病。有 晚期PCa的治疗选择非常有限。因此，必须确定 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能够 区分侵袭性和惰性PCa，同时建立有效的治疗方式 对于那些有高风险发展为转移性癌症的患者。我们的初步结果 表明神经纤毛蛋白-2（NRP 2）可能通过调节前列腺癌的整体细胞凋亡而成为侵袭性前列腺癌的介导因子。 促进癌症所需的基因转录。从机制上讲，NRP 2可以从 ER通过逆行转运到达核膜，稳定转录机制 这是癌症促进基因表达所必需的。根据这些新的观察，我们 假设核NRP 2对转录所需的基因至关重要， PCa的进展因此，NRP 2不仅是侵袭性PCa的预测因子，而且也是侵袭性PCa的靶点。 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NRP 2如何与细胞核相互作用的潜在机制 PCa细胞中的转录因子，并促进其活性。我们还将确定使用队列 核NRP 2是否可以作为一个预后因子，这可以区分 惰性前列腺癌和侵袭性前列腺癌的区别目标2将集中在分子机制如何 NRP 2迁移到核膜，并确定是否抑制这种转运， 阻止前列腺肿瘤生长。总之，我们的建议将决定核NRP 2 促进PCa，因此可以是侵袭性PCa的有效预测因子。此外，它将识别 靶向NRP 2轴如阻断其核转运是否是有效的治疗方法 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.