在前列腺癌細胞中，水解磷酸脂自泌機轉調控淋巴管生成因子的訊號傳遞路徑

Abstract

在臨床研究中發現，前列腺癌惡化轉移和淋巴管新生 (Lymphangiogenesis)有一定的相關性。淋巴管生成因子 (VEGF-C)已知是造成淋巴管新生主要的蛋白質在本實驗的研究發現，在不同前列腺癌細胞株中，水解磷酸脂 (Lysophosphatidic acid) 會刺激淋巴管生成因子的轉錄和轉譯。在更進一步的研究中發現，水解淋酸脂的受器LPA1和LPA3會藉著調控過氧化物的生成 (Reactive Oxygen Species) 正向調控轉錄因子LEDGF的生成，最後刺激淋巴管生成因之的生成。不僅如此，結果也發現前列腺癌細胞中生成水解淋酸脂的酵素ATX也參與淋巴管生成因子 的調控。此發現有助於提供未來前列腺癌標把藥物治療的設計，將可能有效的阻止前列腺癌後期的淋巴轉移。

ABSTRACT Clinical evidence suggests that lymphangiogenesis and lymphatic metastasis are important processes during the progression of prostate cancer. Vascular endothelial growth factor (VEGF)-C was shown to be a key regulator in these processes. Our previous studies demonstrated that lysophosphatidic acid (LPA), a low-molecular-weight lipid growth factor, enhances VEGF-C expression in human endothelial cells. We previously demonstrated that the LPA receptor plays an important role in lymphatic development in zebrafish embryos. However, the effects of LPA on VEGF-C expression in prostate cancer are not known. Herein, we demonstrate that LPA up-regulated VEGF-C expression in three different human prostate cancer cell lines. In PC-3 human prostate cancer cells, the enhancing effects of LPA were mediated through both LPA1 and LPA3. In addition, reactive oxygen species (ROS) production and lens epithelium-derived growth factor (LEDGF) expression were involved in LPA1/3-dependent VEGF-C expression. Furthermore, autotaxin (ATX), an enzyme responsible for LPA synthesis, also participates in regulating VEGF-C expression. By interrupting LPA1/3 of PC-3, conditioned medium (CM) -induced human umbilical vein endothelial cell (HUVEC) lymphatic markers expression was also blocked. In summary, we found that LPA secreted by PC-3 cells enhanced VEGF-C expression through activating LPA1/3-, ROS-, and LEDGF-dependent pathways. These novel findings could potentially shed light on developing new strategies for preventing lymphatic metastasis of prostate cancer.