前列腺癌特异性PSA糖基的鉴定及其在前列腺癌发生发展中的机制研究

Prostate cancer is the most common cancer in western countries, its morbidity and mortality ranked first and second, respectively. In recent years, trends in prostate cancer incidence is rising fast in China, has become the Ninth tumor that cause male death. PSA is most frequently used biomarker for early diagnosis of prostate cancer; however, due to its low specificity and sensitivity, its wide use has resulted in over diagnosis and over treatment of prostate cancer. With the development of modern omics technologies, a series of new biomarkers and mechanisms have been identified for prostate cancer. However, none of these new biomarkers have surpassed the diagnose efficiency of PSA. Developing more effective biomarkers is urgently needed in clinic. Glycosylation alterations are a common change in the process of cancer development. Many glycans were used in clinic as a cancer biomarker. PSA is a prostate specific glycoprotein, its glycosylation changes and underlying mechanism in prostate cancer remain unclear. Our previous studies have found that PSA glycan profiles of prostate cancer differs significantly from that of normal sample. This project is to systematically elucidate PSA glycan profiles both in normal and in prostate cancer patients, identify prostate cancer specific PSA glycans, illustrate the function of these glycans in the process of prostate cancer initiate and progression, explore the possibility of its application in prostate cancer diagnosis biomarker in clinic. The final goal of this project is to develop better biomarkers for prostate cancer diagnosis in China, at the same time, provide better targeted therapy for prostate cancer.

前列腺癌是男性常见的恶性肿瘤。近年来，我国前列腺癌的发病率呈快速上升趋势，已成为男性死亡第九位的肿瘤。PSA是其常用的早期诊断标志物，但因其敏感性和特异性难兼顾，其广泛应用导致了前列腺癌的过度诊断与治疗。寻找更好的早期诊断标志物并阐明其机制是临床急需解决的问题。蛋白糖基化的改变是细胞癌变过程的常见现象，PSA作为前列腺特异性糖蛋白，其糖基化在前列腺癌中的特征及其在前列腺癌发生中的作用和机制目前尚不清楚。我们前期研究建立了利用超高压液相色谱-质谱来分析、鉴定蛋白糖基图谱的方法，并运用此方法发现前列腺癌PSA糖基与正常人存在显著差异。本项目旨在通过系统解析正常与前列腺癌PSA糖基化图谱特征，鉴定前列腺癌特异性PSA糖基，阐明其在前列腺癌发生、发展中的作用及机制，探索其作为前列腺癌早期诊断标志物的可行性，为中国前列腺癌提供更好的诊断标志物，并为前列腺癌的分子靶向治疗提供基础。

前列腺癌是男性常见的恶性肿瘤。近年来，我国前列腺癌的发病率呈快速上升趋势，已成为男性死亡第九位的肿瘤。血清PSA是目前前列腺癌早期诊断与疗效监测的重要生物标记物，但因其敏感性和特异性难兼顾，其广泛应用导致了前列腺癌的过度诊断与治疗。寻找更好的早期诊断标志物并阐明其机制是临床急需解决的问题。蛋白糖基化的改变是细胞癌变过程的常见现象，PSA作为前列腺特异性糖蛋白，其糖基化在前列腺癌中的特征及其在前列腺癌发生中的作用和机制目前尚不清楚。本项目通过收集正常(非前列腺癌)与低/中/高危前列腺癌患者前列腺按摩后尿液，纯化了其中的PSA， 解析了前列腺癌和正常人群中前列腺按摩后尿液中PSA（EPS-Urine PSA）的糖基图谱，发现其中两个糖基（FA2和 FM5A2G2S1）在前列腺癌患者按摩后尿液中PSA的糖基修饰中的含量显著增高，并且FA2的含量同前列腺癌分级的增高呈显著正相关性。另外，血清PSA（sPSA）在不同级别的前列腺癌中没有明显差异，但是sPSA与EPS-Urine PSA（uPSA）的比值（s/uPSA）随着前列腺癌的级别的增高而增高，并且s/uPSA在PSA诊断灰区（PSA在4-20ng/ml之间）能更好地诊断前列腺癌。在进一步机制中，我们研究发现前列腺癌组织中的糖基转移酶B4GALNT4的表达显著升高，B4GALNT4可以通过上调PDK1的表达而激活PI3K信号通路，从而促进前列腺癌的发生和发展。因此，该项目的研究成果为前列腺癌的精确诊断，尤其是在PSA灰区的诊断提供了新的方法，并且为前列腺癌的治疗提供了新的思路。