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Title: | 紫檀芪經由 FABP5 訊號路徑抑制肥胖促進腸癌細胞遷移 Pterostilbene inhibits adipocyte conditioned-medium-induced colorectal cancer cell migration through targeting FABP5 related signaling pathway |
Authors: | Nien-Chi Chen 陳念琦 |
Advisor: | 潘敏雄 |
Keyword: | 結腸直腸癌(colorectal cancer),肥胖,fatty acid-binding protein 5 (FABP5),紫檀? pterostilbene (PTS),adipocyte conditioned-medium (aCM), colorectal cancer (CRC),obesity,fatty acid-binding protein 5 (FABP5),pterostilbene (PTS),adipocyte conditioned-medium (aCM), |
Publication Year : | 2018 |
Degree: | 碩士 |
Abstract: | 結腸直腸癌 (colorectal cancer) 是目前備受重視的健康議題,其發病原因與飲食習慣、肥胖及發炎性大腸疾病相關,而肥胖可能透過提高促發炎因子如 tumor necrosis factor-α (TNF-α)、interleukin-6 (IL-6) 及調節脂肪酸攝取與運送的脂肪酸結合蛋白 fatty acid-binding protein 5 (FABP5) 之表現而促進結腸直腸癌的發展。紫檀芪 (pterostilbene, PTS) (3,5-dimethoxy-4’hydroxystilbene) 隸屬於多酚類化合物 stilbenoids,存在於蔓越莓及藍莓中,是 resveratrol 的相似物,已知具有抗氧化、降低膽固醇、抗肥胖及抗腫瘤的活性,因此本研究將進一步評估在 adipocyte conditioned-medium (aCM) 誘導人類腸癌細胞 HT29 惡性轉型過程中,PTS 的預防功效以及調節分子機制。結果證實,PTS 可以抑制aCM 所刺激的轉錄因子 nuclear factor-kappa B (NF-kB)、b-catenin 及 peroxisome proliferator-activated receptor g(PPAR-g) 的活性,而這些轉錄因子經由其上游的 phosphoinositide 3-kinase (PI3K)、protein kinase B (Akt)、p38 mitogen-activated protein kinase (p38 MAPK)、extracellular signal-regulated kinase (ERK) 及 c-Jun N-terminal kinases 1/2 (JNK1/2) 等訊息傳遞路徑所活化,這些路徑可以藉由給予 PTS 後被抑制,繼而減少腸癌細胞中 FABP5 的基因及蛋白質表達,同時也降低了促轉移因子 vascular endothelial growth factor (VEGF)、matrix metalloproteinase-2 (MMP2) 和 MMP9 的蛋白質表現,並且能進一步抑制 MMP2 和 MMP9 的酵素活性,更減少分泌到胞外的 TNF-a。本實驗亦發現,利用經 TNF-a 抗體中和後的 aCM 培養 HT29 之後,能使原本被誘發的 FABP5、VEGF、MMP2 與 MMP9 之表現具有減少的現象。綜合以上結果建議,PTS 可以從基因層面調控 FABP5 的訊號途徑,抑制肥胖微環境所誘導的人類腸癌細胞之遷移,進而達到減緩肥胖相關之腸癌惡質化。 Colorectal cancer (CRC) is a worldwide health issue related to diet habit, obesity and inflammatory bowel disease (IBD). Obesity could promote CRC development by increasing the secretion of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and the expression of fatty acid-binding protein (FABP5). Pterostilbene (PTS) (3,5-dimethoxy-4’hydroxystilbene), a natural dimethylated analog of resveratrol, is a phenolic compound with diverse pharmacologic activities including anti-inflammatory, antioxidant, anti-obesity and antitumor. However, its potential for inhibiting obesity-related CRC remains unclear. Our study evaluated the mechanism of inhibitory effects of PTS on adipocyte conditioned-medium (aCM)-induced malignant transformation in HT29 colorectal adenocarcinoma cells. Results showed that PTS could downregulate the expression of aCM-induced FABP5 and pro-metastasis factors such as vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP2), MMP9 and extracellular tumor necrosis factor alpha (TNF-a via inhibiting aCM-induced nuclear factor-kappa B (NF-kB), b-catenin and peroxisome proliferator-activated receptor g(PPAR-g). Moreover, PTS can suppress aCM-stimulated phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinases 1/2 (JNK 1/2) signaling pathways activation which are upstream of NF-kB, b-catenin and PPAR-g. Based on our findings, we suggested that PTS could aliviate adiposity-induced cachexia in CRC via inihibiting cell migration through downregulating FABP5 gene expression. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/71873 |
DOI: | 10.6342/NTU201804181 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 食品科技研究所 |
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