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

Prosaposin：非裔美国人前列腺癌进展的新型生物标志物

• 批准号: 8288659
• 负责人: SHAHRIAR KOOCHEKPOUR
• 金额: $ 41.41万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288659
• 关键词: Affect; African American; Aftercare; Age; Apoptotic; Behavior; Benign; Biological; Biological Assay; Biological Markers; Cancer Etiology; Caucasians; Caucasoid Race; Cell Line; Cell Survival; Cells; Cessation of life; Characteristics; Clinical; Data; Development; Diagnosis; Disease; Disease Progression; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Gland; Gleason Grade for Prostate Cancer; Health Services Accessibility; In Vitro; Incidence; Indolent; Investigation; Laboratories; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Modeling; Molecular; NOD/SCID mouse; Neoplasm Metastasis; Nude Mice; Organ; PC3 cell line; Patients; Pattern; Peptide Hydrolases; Phenotype; Pilot Projects; Primary Neoplasm; Prognostic Factor; Prostate; Proteins; RNA Interference; Radical Prostatectomy; Risk Factors; Sampling; Screening for Prostate Cancer; Screening procedure; Serum; Specimen; Staging; Staining method; Stains; TNM; Testing; Time; Tissues; Tumor Markers; Undifferentiated; Xenograft procedure; base; cancer cell; cancer diagnosis; cell motility; clinically significant; follow-up; implantation; improved; mRNA Expression; men; migration; mortality; novel; overexpression; prognostic; protein expression; racial difference; subcutaneous; tissue resource; tumor; tumor growth; tumor progression; tumor xenograft

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.

前列腺癌（PCA）是美国男性与癌症相关的第二大原因的主要原因，是最大的 非洲裔美国人的任何恶性疾病的种族差异，发病率提高1.6-1.9倍，2- 死亡率是高加索人的3倍。非裔美国人的PCA提出了更先进的临床 阶段和侵略性肿瘤。需要PCA生物标志物来改善对临床意义的早期检测 肿瘤并区分酸性或缓慢的肿瘤与更具侵略性的肿瘤。在我们寻找肿瘤 标记，我们将prosaposin（PSAP）作为分泌的蛋白质克隆，并在转移性中发现了其过表达 PCA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 PCA细胞中的迁移和侵袭和上调降解基质蛋白水解酶的表达。在 与原发性PCA相比，高加索人，转移性PCA的血清PSAP水平升高 前列腺组织。此外，器官夹层和 局部侵入性肿瘤。与高加索人相反，我们在非裔美国人的试点研究表明a）组织 Gleason 4/5级模式的未分化肿瘤中PSAP的表达明显高于 Gleason D级3或良性腺体（BPH）和B）血清PSAP水平较高 局部侵入性（III/IV期）肿瘤比在器官构造的（I/II期）肿瘤中，该肿瘤正相关 疾病进展。基于这些观察结果，我们假设PSAP有助于PCA 进展，具有新型生物标志物的特征 非裔美国人患者的侵略性。为了检验我们的假设，我们提出以下目的：1）定义 血清PSAP作为PCA进展或侵略性的临床意义 美国人2）确定PSAP的组织表达与临床和组织病理学之间的关联 非洲裔美国人PCA进展或侵略性的预测因素或预后； 3）确定 PSAP与PSAP过表达的PSAP与侵入性和转移表型之间的关联 非裔美国人PCA细胞。我们将使用免疫组织化学分析和三明治-ELISA分析 量化大型组织和血清样品中的PSAP表达水平，并确定它们 与PCA侵略性和进展的临床组织病理学预测因子或预后 在非裔美国人。我们还将测试PSAP表达增加或降低对肿瘤生长的影响 非裔美国人的皮下和原位肿瘤异种移植物的速率和自发转移能力 派生的PCA细胞。在本提案的结论中，我们将定义临床和组织病理学 PSAP作为PCA进展和/或侵略性的生物标志物在非洲裔美国人中的重要性 可以进一步用于临床发展。