戴奧辛受器在前列腺癌細胞中對於水解磷酸脂誘導的血管內皮生長因子訊息傳遞路徑影響之研究

Abstract

水解磷酸脂(LPA)存在正常人體血清中而在癌症病患中濃度大增。其在癌症發生過程中，會誘發血管內皮生長因子(VEGF-A 及VEGF-C)表現。在LPA誘導VEGF-A表達的訊息路徑中，1α-缺氧誘發因子(HIF-1α)與芳香烴受體核轉位蛋白(ARNT)聚合形成缺氧誘發因子(HIF-1)，進而誘發VEGF-A表現。然而，HIF-1α是否調控VEGF-C表現卻鮮為人知。由於ARNT也會與戴奧辛受體(AhR)聚合成複合物，因此我們假設AhR可藉由與HIF-1α競爭結合至ARNT，進而抑制LPA所誘導VEGF-A 及VEGF-C表現。於本研究中，我們調查AhR如何影響LPA誘導VEGF-A 及VEGF-C表現及闡明LPA誘導VEGF-A 及VEGF-C表現的分子機制。結果發現，在PC-3前列腺癌細胞株中，當AhR被過量表達或是被3-甲基膽蔥（3-methylcholanthrene, 3-MC）所活化皆會抑制LPA誘導VEGF-A 及VEGF-C表現。此外，磷脂酰肌醇3-激酶(PI3K)、HIF-1α以及ARNT皆參與調控LPA誘導VEGF-A 及VEGF-C表現。這些結果顯示，AhR可能藉由減弱LPA所刺激的HIF-1訊息路徑，因而抑制VEGF-A 與VEGF-C表現。本研究的重要性在於未來可能利用調節AhR，進而調控血管新生以及淋巴管新生，因此AhR具有成為前列腺癌細胞轉移治療標的之潛力。

Lysophosphatidic acid (LPA) which exists in normal human serum and reaches higher concentration in cancer patients can induce expression of vascular endothelial growth factors (VEGF-A and VEGF-C), thereby modulating angiogenesis and lymphangiogenesis. In the pathway of LPA-induced VEGF-A expression in PC-3 prostate cancer cells, hypoxia-inducible factor-1 alpha (HIF-1α) dimerizes with aryl hydrocarbon receptor nuclear translocator (ARNT, identical to HIF-1β) to form hypoxia-inducible factor-1 (HIF-1), then regulating VEGF-A expression. However, the effects of HIF-1 signaling on LPA-induced VEGF-C expression have not been determined. ARNT also dimerizes with aryl hydrocarbon receptor (AhR). Since ARNT is a common dimerization partner of AhR and HIF-1α, we hypothesized that AhR has the potential to suppress LPA-induced VEGFs expression in PC-3 prostate cancer cells by competing with HIF-1α for ARNT. Herein, we determined the effects of AhR signaling on LPA-induced VEGFs expression and the underlying signaling pathway of LPA-induced VEGFs expression. AhR over-expression or activation of AhR by a selective AhR modulator (SAhRM) called 3-methylcholanthrene (3-MC) inhibited LPA-induced VEGFs expression in PC-3 cells. In addition, LPA-induced VEGF-A and VEGF-C expressions were both regulated by HIF-1α, ARNT and through activation of the phosphatidylinositol 3-kinase (PI3K) signaling. The results obtained from this study indicate that AhR inhibits LPA-induced VEGFs expression in PC-3 prostate cancer cells possibly by attenuating LPA-stimulated HIF-1 signaling pathway. Furthermore, these findings also suggest that AhR is likely to become a therapeutic target for prevention of prostate cancer metastasis.