腫瘤細胞產生VEGF-C並活化其受器VEGFR3誘導淋巴管增生。但其受器也在許多惡性腫瘤細胞上被發現(例如A549)。至今發現VEGF-C活化VEGFR3藉由活化下游p38/MAPK路徑促使細胞移動。然而，VEGF-C如何透過VEGFR3促使細胞增生之機制還不清楚。由我們的初步實驗結果發現，加入150 ng/ml的VEGF-C促使增加A549細胞數目。基於此結果，本篇研究目的是釐清VEGF-C如何透過VEGFR3及其下游機制促使腫瘤細胞增生。利用生化、功能及定量蛋白質體分析其可能之機制。藉由測定Akt磷酸化程度並且排除VEGF-C會誘導細胞存活之可能性；同時藉由流式細胞儀、螢光染色及西方墨點法偵測細胞增生，由結果得知VEGF-C促使細胞週期由Sub G0進入S時期、增加BrdU+細胞數目及增加Rb磷酸化，證實VEGF-C會促使細胞周期進行。最後藉由定量核蛋白質分析，發現42個蛋白質可能參與VEGF-C調控之細胞週期進行。例如，VEGF-C促使cell cycle and apoptosis regulatory protein 1 (CARP-1)和 histone H2A and H2B 表現量降低、增加 histone H1、catenin delta-1、serine/ threonine-protein kinase 4及ADP-ribosylation factor-like protein 2表現. 兩種VEGFR3抑制劑(Cpd. 1250及VEGFR3/Fc) 逆轉VEGF-C降低CARP-1表現、增加BrdU+細胞及減少細胞凋亡期之細胞數目. Cpd. 1250 抑制細胞增生，但單獨處理會增加Akt磷酸化及Ebp-1表現進而促使細胞存活。由蛋白質體及生化分析結果得知，高濃度的VEGF-C處理會藉由調控CARP-1/Rb活化路徑及histone調節染色體結構進而加速細胞週期由G0進入S期。不像VEGFR3/Fc之反應，Cpd. 1250是會結合到多重目標的抑制劑除了抑制藉由活化VEGFR3之細胞增生，同時增加非VEGFR3下游Akt磷酸化路徑及Ebp-1表現，進而促進A549細胞存活。總結來說，VEGFR3抑制劑(Cpd. 1250和VEGFR3/Fc)可能是可用於對於晚期惡性腫瘤細胞增生及轉移一種好的治療方式，同時並未具有細胞毒性。

Vascular endothelial growth factor-C (VEGF-C) which induces lymphangiogenesis through VEGF receptor 3 (VEGFR3) can be produced from tumor cells. In addition, VEGFR3 is also found in various tumor cells (such as A549 cells). Up to date, it is known that activation of VEGFR3 by VEGF-C induced cell migration of A549 through a p38/MAPK pathway. However, it is not clear whether VEGF-C induced tumor cell proliferation. Since our preliminary data showed the increase of cell counts by VEGFC at 150 ng/ml, the purpose of this study was to explore the action mechanism of VEGFC on cell proliferation by combination of biochemical, functional and quantitative proteomic assays. To exclude the possibility that the increase of cell counts by VEGF-C was due to the increase of cell survival, the effect of VEGF-C on Akt phosphorylation was further examined. FAScan analysis, immunofluorescent analysis, and western blotting assay showed VEGF-C-induced increases in cell population at G1/S phase, BrdU-positive cells and Rb phosporylation. The data confirmed the induction of cell cycle shift from G0 to G1 phase by VEGF-C. Finally, subcellular proteomic analysis coupled with quantitative technology revealed about 42 nuclear proteins which might be involved in VEGF-C-induced shift in cell cycle. For example, cell cycle and apoptosis regulatory protein 1 (CARP-1), histone H2A and H2B were decreased by VEGF-C; histone H1, catenin delta-1, serine/ threonine-protein kinase 4, and ADP-ribosylation factor-like protein 2 were increased by VEGF-C. VEGFR3 antagonists (Cpd. 1250 and VEGFR3/Fc) reversed VEGF-C-induced increases in CARP-1 expression, BrdU-positive cell, cell population in apoptotic phase. Cpd. 1250 inhibited cell proliferation and also increased pAkt and Ebp-1 to maintain cell survival. Both proteomic and biochemical results suggest that high concentrations of VEGF-C accelerated the progression of cell cycle from G0 to G1/S through a CARP-1/Rb-mediated pathways, histone-mediated chromatin remodeling. Unlike VEGFR3/Fc, Cpd. 1250 was a multitarget antagonist that inhibited cell proliferation through a VEGFR3-dependnet pathway and increased phosphorylation of Akt and expression of Ebp-1 to maintain cell survival through a VEGFR3-independent pathway in A549 cells. In addition, VEGFR3 antagonists (Cpd. 1250 and VEGFR3/Fc) may be a good current therapy to inhibit malignant cancer proliferation and metastasis at local sites with no cytotoxicity.

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