n-3多元不飽和脂肪酸對腫瘤相關巨噬細胞誘導前列腺癌進展之影響

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題名:	n-3多元不飽和脂肪酸對腫瘤相關巨噬細胞誘導前列腺癌進展之影響 Effects of n-3 polyunsaturated fatty acids on prostate cancer progression induced by tumor-associated macrophages
作者:	李正中 Li, Cheng-Chung
貢獻者:	保健營養學研究所葉松鈴
關鍵詞:	EPA;DHA;前列腺癌;腫瘤相關巨噬細胞;PPAR-γ;NF-κB EPA;DHA;prostate cancer;TAM;PPAR-γ;NF-κB
日期:	2016
上傳時間:	2021-10-29 16:07:55 (UTC+8)
摘要:	Eicosapentaenoic acid (EPA)和docosahexaenoic acid (DHA)為魚油中最主要的n-3多元不飽和脂肪酸(polyunsaturated fatty acids, PUFA)，與降低罹患前列腺癌風險有關。腫瘤相關巨噬細胞(tumor-associated macrophages, TAM)為最主要浸潤於腫瘤微環境中的免疫細胞，其浸潤程度與前列腺癌之預後呈負相關。然而n-3 PUFA對於TAM所誘導之前列腺癌細胞進展的影響機制尚未了解。本研究觀察EPA、DHA或peroxisome proliferator-activated receptor (PPAR)-γ的拮抗劑(GW9662)添加對於與TAM-like M2巨噬細胞共同培養的前列腺癌PC-3細胞影響，EPA/DHA的添加顯著降低PC-3細胞遷移及侵犯的能力，且顯著增加PPAR-γ的DNA-binding活性及細胞質中inhibitory factor κBα (IκBα)的蛋白質表現，並抑制nuclear factor (NF)-κB p65的轉錄能力，然而在事先與GW9662共同培養的組別，EPA/DHA的效果皆消失。在動物實驗中將前列腺癌PC-3細胞打入BABL/c雄性裸鼠右腹側皮下，並隨機分成三組，依照AIN-93G飼料之比例配方餵予含7%脂肪的飲食，給予大豆油為Control (C)，利用魚油取代部分大豆油將飲食中n-3/n-6 PUFA調整成1 : 4作為low fish oil (LF)組，n-3/n-6 PUFA調整成1 : 2作為high fish oil (HF)組，八周後犧牲。實驗結果顯示以魚油部分取代大豆油的組別其腫瘤體積、TAM浸潤程度及M2巨噬細胞的比例皆顯著低於C組。與C組相比，LF及HF組前列腺腫瘤皆有顯著增加PPAR-γ的DNA-binding活性及降低NF-κB的活化程度，並且也降低了其下游之促腫瘤進展之基質金屬蛋白酶(matrix metalloproteinases-9、血管內皮生長因子(vascular endothelial growth factor,VEGF)和VEGF受器的表現。本研究結果顯示n-3 PUFA (EPA/DHA)可延緩前列腺癌的進展，其可能機制與增加PPAR-γ的DNA-binding活性、降低TAM浸潤及其M2巨噬細胞的比例有關。 Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the major n-3 polyunsaturated fatty acids (PUFA) in fish oil that decrease the risk of prostate cancer. Tumor-associated macrophages (TAM) are the main leukocytes of intratumoral infiltration, and increased TAM correlates with poor prostate cancer prognosis. However, the mechanism of n-3 PUFAs on prostate cancer cell progression induced by TAM is not well understood. In this study, PC-3 prostate cancer cells were pretreated with EPA, DHA, or the peroxisome proliferator-activated receptor (PPAR)-γ antagonist, GW9662, before exposure to conditioned medium (CM). CM was derived from TAM-like M2-polarized THP-1 macrophages. EPA/DHA administration decreased migration and invasion of PC-3 cells. The PPAR-γ transcriptional activity and cytosolic inhibitory factor κBα (IκBα) protein expression increased while the nuclear factor (NF)-κB p65 transcriptional activity and nuclear NF-κB p65 protein level decreased in PC-3 cells incubated with CM in the presence of EPA/DHA. Pretreatment with GW9662 abolished the favorable effects of EPA/DHA on PC-3 cells. In the animal study, BABL/c nu/nu mice (N=30) were inoculated with 5×105 PC-3 cells in the right flank subcutaneously. Mice in the control (C) group were fed with a semi-purified diet with 7% soybean oil. The n-3/n-6 PUFA ratio of the LF group was 1:4, the ratio of the HF was 1:2. After feeding the respective diets for 8 weeks, all mice were sacrificed. The results showed that groups with fish oil (FO) enriched diets had lower tumor volume and downregulated TAM infiltration and M2 macrophage polarization in the prostate tumor microenvironment. Compared to the C group, FO groups had higher PPAR-γ transcriptional activity and decreased NF-κB activation that may consequently have reduced in protein expression of matrix metalloproteinases-9, vascular endothelial growth factor (VEGF), VEGFR. This study indicated that n-3 PUFA (EPA/DHA) attenuated prostate cancer progression at least partly by upregulating PPAR-γ transcriptional activity and decreased TAM infiltration and M2 macrophage polarization.
描述:	博士指導教授：葉松鈴
資料類型:	thesis
顯示於類別:	[保健營養學系暨研究所] 博碩士論文

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