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標題: | 水解磷酸脂對於前列腺癌的淋巴管新生機制之研究 Regulatory Mechanism of Lysophosphatidic Acid-Mediated Lymphangiogenesis in Prostate Cancer |
作者: | Yueh-Chien Lin 林岳謙 |
指導教授: | 李心予 |
關鍵字: | 前列腺癌,水解磷酸脂,血管內皮生長因子-C,鈣網蛋白,真核起始因子2α,淋巴管新生, PCa,LPA,VEGF-C,CRT,eIF2α,lymphangiogenesis, |
出版年 : | 2018 |
學位: | 博士 |
摘要: | 水解磷酸脂 (lysophosphatidic acid, LPA) 是一種具有生物活性的脂質性生長因子,主要存在於血清與血小板。LPA 透過結合其具有專一性的 G 蛋白偶合受體 (G-protein-coupled receptors) 包括 LPA1 ~ LPA6,來調控各式各樣的生理反應,例如癌細胞的生長,血管新生和淋巴管新生 (lymphangiogenesis)。我們之前的研究指出 LPA 可以在前列腺癌細胞中提昇淋巴生長因子“血管內皮生長因子-C” (vascular endothelial growth factor-C, VEGF-C) 的表現。LPA 已證實可調控具有多功能的伴隨蛋白 “鈣網蛋白”(calreticulin, CRT) 的表現,但是此一調控是否對於前列腺癌的進程尚待釐清。因此,此研究主要是探討在前列腺癌中 CRT 是否參與調控 LPA 作用產生的 VEGF-C 表現和淋巴管新生。在 PC-3 癌細胞中調降 CRT 的表現明顯地降低 LPA 刺激產生的 VEGF-C 表現。此外,該反應是透過活化 LPA 受器 LPA1 和 LPA3,活性氧物種 (reactive oxygen species, ROS) 的產生和真核起始因子2α (eukaryotic translation initiation factor 2α, eIF2α) 的磷酸化。腫瘤異種移植之小鼠實驗更近一步證實,降低 CRT 可以有效地抑制前列腺腫瘤的生長和淋巴管生成。值得注意地,臨床檢體的證據指出 LPA生成酵素“自分泌運動因子”(autotaxin, ATX) 與 CRT 的表現具有正相關性,且 CRT 的表現量與腫瘤中的 VEGF-C 和淋巴管密度呈現高度正相關性。更重要地,使用 LPA 受器之藥理拮抗劑在腫瘤移植的裸鼠上,有效地降低腫瘤內的淋巴管密度和淋巴結轉移。我們的研究證實了 CRT 參與 LPA 刺激 VEGF-C 表現的機制,且該機制對於前列腺癌的發展至關重要。因此,未來針對前列腺癌細中 LPA 相關的訊息傳遞路徑是一種具有潛力的對抗前列腺癌的治療方針。 Lysophosphatidic acid (LPA) is a bioactive lipid growth factor, which is present in high levels in serum and platelets. LPA binds to its specific G-protein-coupled receptors, including LPA1 to LPA6, thereby regulating various physiological functions, including cancer growth, angiogenesis, and lymphangiogenesis. Our previous study showed that LPA promotes the expression of the lymphangiogenic factor vascular endothelial growth factor (VEGF)-C in prostate cancer (PCa) cells. Interestingly, LPA has been shown to regulate the expression of calreticulin (CRT), a multifunctional chaperone protein, but the roles of CRT in PCa progression remain unclear. Here we investigated the involvement of CRT in LPA-mediated VEGF-C expression and lymphangiogenesis in PCa. Knockdown of CRT significantly reduced LPA-induced VEGF-C expression in PC-3 cells. Moreover, LPA promoted CRT expression through LPA receptors LPA1 and LPA3, reactive oxygen species (ROS) production, and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). Tumor-xenografted mouse experiments further showed that CRT knockdown suppressed tumor growth and lymphangiogenesis. Notably, clinical evidence indicated that the LPA-producing enzyme autotaxin (ATX) is related to CRT and that CRT level is highly associated with lymphatic vessel density and VEGF-C expression. Interestingly, the pharmacological antagonist of LPA receptors significantly reduced the lymphatic vessel density in tumor and lymph node metastasis in tumor-bearing nude mice. Together, our results demonstrated that CRT is critical in PCa progression through the mediation of LPA-induced VEGF-C expression, implying that targeting the LPA signaling axis is a potential therapeutic strategy for PCa. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/69392 |
DOI: | 10.6342/NTU201801409 |
全文授權: | 有償授權 |
顯示於系所單位: | 生命科學系 |
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