Study on the role of lysophosphatidic acid in the seminal fluids and its related molecules in the development of prostate cancer

本研究旨在阐明溶血磷脂酸(LPA)及其相关分子在前列腺癌发生发展中的作用。前列腺组织标本取自10例局限性前列腺癌和7例浸润性膀胱癌患者。用激光捕获显微解剖技术分离癌细胞、高级别上皮内瘤变(HGPIN)、良性增生性腺体、正常腺体及其相应的间质细胞。以膀胱癌患者前列腺癌患者的正常腺体及其相应的间质为对照。定量检测三种LPA受体LPA1、LPA2、LPA3、两种LPA合成酶(ATX、AGK)和LPA降解酶前列腺酸性磷酸酶(PAP)的mRNA水平。我们还研究了人前列腺癌LNCaP、PC-3和DU-145细胞中LPA1的基因表达水平。与良性腺体相比，HGPIN和癌上皮中LPA1的基因表达水平显著降低。与对照组良性腺体相比，癌组织中LPA3基因表达水平升高。LNCaP细胞主要表达LPA3、AGK和PAP基因，PC-3和DU-145细胞主要表达LPA1和ATX基因。在BPH中，间质中AGK和上皮中PAP的表达同时升高。通过LPA3的LPA刺激可能在前列腺癌的发生发展中起关键作用。主要的LPA受体类型(LPA3到LPA1)的转换可能参与疾病的进展和/或雄激素依赖性。

This study was carried out to elucidate the role of lysophosphatidic acid (LPA) and LPA-relating molecules in the development and progression of prostate cancer. Prostate tissue samples were surgically obtained from 10 patients with localized prostate cancer and 7 patients with invasive bladder cancer. Cancer cells, high grade intraepithelial neoplasia (HGPIN), benign hyperplastic glands, normal glands, and their corresponding stromal cells were isolated by laser capture microdissection. Normal glands and its corresponding stroma from the prostate of bladder cancer patients were referred as a control. mRNA levels of three LPA receptors, LPA1, LPA2, LPA3, two LPA-synthetic enzymes, autotaxin (ATX), acylglycerol kinase (AGK), and a LPA-degradation enzyme, prostatic acid phosphatase (PAP), were quantitatively assessed. Gene expression levels were also evaluated in human prostate cancer LNCaP, PC-3, and DU-145 cells.LPA1 mRNA level was significantly decreased in HGPIN and cancer epithelia as compared to the benign glands. LPA3 mRNA level was elevated in cancer epithelia as compared to control benign glands. LPA3, AGK, and PAP gene expressions were predominant in LNCaP cells while LPA1 and ATX gene expressions were predominant in PC-3 and Du-145 cells. In BPH, elevated expression of AGK in stroma and PAP in epithelia was simultaneously found. LPA stimuli via LPA3 may play a pivotal role in the development of prostate cancer. Switching of predominant type of LPA receptors (LPA3 to LPA1) may be involved in the progression and/or androgen independence.