Prosaposin: A Novel Biomarker of Prostate Cancer Progression in African Americans

前列腺癌(PCA)是美国男性癌症相关死亡的第二大原因，是最大的 在非裔美国人中，任何恶性疾病的种族差异，发病率高出1.6-1.9倍，2- 死亡率是高加索人的3倍。非裔美国人的PCa呈现出更先进的临床 分期和侵袭性肿瘤。需要PCA生物标记物来改善临床有意义的早期检测 并将惰性或生长缓慢的肿瘤与更具侵袭性的肿瘤区分开来。在我们寻找肿瘤时 标记，我们克隆了分泌型蛋白丙皂苷(PSAP)，并发现其在转移性肿瘤中的高表达。 前列腺癌细胞和组织。以前，我们证明了PSAP和/或其活性分子衍生物增加 前列腺癌细胞的迁移、侵袭和上调基质降解蛋白水解酶的表达。在……里面 与原发或正常相比，转移性前列腺癌患者血清PSAP水平升高 前列腺组织。此外，在器官受限和器官受限之间，血清PSAP水平没有差异。 局部侵袭性肿瘤。与高加索人不同，我们在非裔美国人中的初步研究表明，a)组织 PSAP在Gleason分级为4/5的未分化肿瘤中的表达显著高于未分化肿瘤 分化肿瘤的Gleason分级d 3或良性腺体(BPH)和b)血清PSAP水平在 局部侵袭性(III/IV期)肿瘤高于器官受限(I/II期)肿瘤，两者呈正相关 随着疾病的发展。基于这些观察，我们假设PSAP对PCA有贡献 并具有鉴别侵袭性肿瘤和非侵袭性肿瘤的新生物标志物的特征 非裔美国人患者中的攻击性。为了验证我们的假设，我们提出了以下目标：1)定义 血清PSAP作为非洲人前列腺癌进展或侵袭性标志物的临床意义 2)确定PSAP的组织表达与临床和组织病理学之间的关系 预测或预测非裔美国人的前列腺癌进展或侵袭性；以及3)决定 PSAP过表达或沉默的侵袭和转移表型与PSAP的相关性 非裔美国人的前列腺癌细胞。我们将使用免疫组织化学分析和夹心ELISA法来 量化大量组织和血清样本中PSAP的表达水平，并确定其 PCa侵袭性和进展性与临床组织病理学指标或预后指标的相关性 在非裔美国人身上。我们还将测试PSAP表达的增加或减少对肿瘤生长的影响 非裔美国人皮下和原位移植肿瘤的发生率和自发转移能力 来源的PCA细胞。在这项提案的结论中，我们将定义临床和组织病理学 PSAP作为非裔美国人前列腺癌进展和/或侵袭性的生物标志物的意义 可进一步用于临床开发。

Prostate cancer (PCa), the second leading cause of cancer-related death in US men, presents the greatest racial disparity of any malignant disease in African Americans, with a 1.6-1.9 times higher incidence rate and 2- 3 times higher mortality rate than Caucasians. PCa in African Americans presents with more advanced clinical stages and aggressive tumors. PCa biomarkers are needed to improve early detection of clinically significant tumors and to distinguish indolent or slow growing tumors from more aggressive ones. In our search for tumor markers, we cloned prosaposin (PSAP) as a secreted protein and discovered its overexpression in metastatic PCa cells and tissues. Previously, we demonstrated that PSAP and/or its active molecular derivatives increase migration and invasion and upregulate matrix-degrading proteolytic enzymes expression in PCa cells. In Caucasians, serum-PSAP levels are increased in metastatic PCa when compared to primary PCa or normal prostate tissues. In addition, there was no difference in serum-PSAP levels between organ-confined and locally-invasive tumors. In contrast to Caucasians, our pilot study in African Americans shows that a) tissue expression of PSAP is significantly higher in undifferentiated tumors with Gleason grade 4/5 pattern than in the differentiated tumors with Gleason grade d 3 or benign glands (BPH) and b) serum-PSAP levels are higher in locally invasive (stage III/IV) tumors than in the organ-confined (stage I/II) tumors which positively correlates with disease progression. Based on these observations, we hypothesized that PSAP contributes to PCa progression and has the characteristics of a novel biomarker discriminating the aggressive tumors from non- aggressive ones in African American patients. To test our hypothesis, we propose the following Aims: 1) Define the clinical significance of serum-PSAP as a marker of PCa progression or aggressiveness in African Americans; 2) Determine the association between tissue expression of PSAP and clinical and histopathological predictors or prognosticators of PCa progression or aggressiveness in African Americans; and 3) Determine the association between PSAP and invasive and metastatic phenotypes in PSAP-overexpressed or -silenced African American PCa cells. We will use immunohistochemical analysis and sandwich-ELISA assays to quantify PSAP expression levels in a large pool of tissue and serum samples and to determine their association with clinicohistopathological predictors or prognosticators of PCa aggressiveness and progression in African Americans. We will also test the effect of increased or decreased PSAP expression on tumor growth rate and spontaneous metastatic ability in subcutaneous and orthotopic tumor xenografts in African American- derived PCa cells. At the conclusion of this proposal, we will have defined the clinical and histopathological significance of PSAP as a biomarker of PCa progression and/or aggressiveness in African Americans that could be further utilized in clinical development.