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標題: | 肝細胞癌之相關研究:
一、肝型脂肪酸結合蛋白促進肝細胞癌之血管新生及細胞移行 二、科羅索酸針對VEGFR2/Src/FAK路徑抑制肝細胞癌之細胞移行 Studies on Hepatocellular Carcinoma (HCC): I. Liver Fatty Acid-Binding Protein (L-FABP) Promotes Cellular Angiogenesis and Migration in Hepatocellular Carcinoma II. Corosolic Acid Inhibits Hepatocellular Carcinoma Cell Migration by Targeting the VEGFR2/Src/FAK Pathway |
作者: | Chung-Yu Ku 辜琮祐 |
指導教授: | 林榮耀(Jung-Yaw Lin),呂紹俊(Shao-Chun Lu) |
關鍵字: | 肝細胞癌,血管新生作用,肝型脂肪酸結合蛋白,血管內皮生長因子,科羅索酸,細胞移行,第二型血管內皮生長因子受體, Hepatocellular carcinoma,angiogenesis,liver fatty acid-binding protein,vascular endothelial growth factor,corosolic acid,migration,vascular endothelial growth factor receptor-2 (VEGFR2), |
出版年 : | 2015 |
學位: | 博士 |
摘要: | 國際上肝細胞癌在癌症發生率中排行第五,在癌症致死率中排行第三。肝細胞癌的生長及進展仰賴於新生血管的形成,而血管內皮生長因子(VEGF)在此過程中扮演非常重要的角色。
肝型脂肪酸結合蛋白(L-FABP)在肝細胞中大量表現,並已知可參與脂質代謝。L-FABP 過度表現已在許多癌症中被發現,但它在肝細胞癌中扮演的角色仍不清楚。本研究中,我們分析了L-FABP 與VEGF 在90 個HCC 患者中的關聯性。我們發現,L-FABP 在肝癌組織中與VEGF-A 呈現正相關性。此外,L-FABP 在異種移植小鼠模式中可顯著促進腫瘤生長及轉移。我們亦討論L-FABP 活性與腫瘤生成的關係:L-FABP 可與細胞膜上脂筏中的VEGFR2 結合,接著活化下游的Akt/mTOR/P70S6K/4EBP1 與Src/FAK/CDC42 路徑,這也使得VEGF-A 表現量增加,並促進血管新生與細胞移行之活性。我們的研究結果證實,L-FABP 可望成為治療肝癌的新目標。 在臨床上,抑制第二型血管內皮生長因子受體(VEGFR2)之活性已被建議作為治療HCC 的重要策略。本研究中,我們發現獼猴桃根部之化合物,科羅索酸(CA),對肝癌細胞表現出顯著的抗癌作用。研究指出, CA 可透過與VEGFR2 上ATP 結合口袋的交互作用,抑制VEGFR2 之活性。 CA 在Huh7 細胞實驗中可抑制性調控VEGFR2/Src/FAK/CDC42 路徑,減少絲狀肌動蛋白(F-actin)之形成,並降低細胞移行能力。在動物實驗中,CA 對腫瘤生長的有效抑制劑量為每隻小鼠給予5 毫克/公斤/天。我們也證實,CA 與蕾莎瓦(Sorafenib)在廣範圍濃度下具有協同效應。 本研究闡明了CA 抗肝癌的細胞分子機制,並建議CA 可作為治療侵襲性肝癌之抗癌藥或佐劑。 Hepatocellular carcinoma (HCC) is the fifth most commonly occurring cancer and the third most common cause of cancer death worldwide. The progression of HCC relies on the formation of new blood vessels, and VEGF is critical in this process. Liver fatty acid-binding protein (L-FABP) is abundant in hepatocytes and known to be involved in lipid metabolism. Overexpression of L-FABP has been reported in various cancers; however, its role in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated L-FABP and its association with vascular endothelial growth factors (VEGFs) in 90 HCC patients. We found that L-FABP was highly expressed in their HCC tissues, and its expression level was positively correlated with that of VEGF-A. Additionally, L-FABP significantly promoted tumor growth and metastasis in a xenograft mouse model. We also studied the mechanisms of L-FABP activity in tumorigenesis: L-FABP was found to be associated with VEGFR2 on membrane rafts and subsequently activate the Akt/mTOR/P70S6K/4EBP1 and Src/FAK/cdc42 pathways. This resulted in up-regulation of VEGF-A expression accompanied by an increase in both angiogenic potential and migration activity. Taken together, our results suggest that L-FABP may be a potential target for HCC chemotherapy. Inhibition of VEGFR2 activity has been proposed as an important strategy for the clinical treatment of hepatocellular carcinoma (HCC). In this study, we identified corosolic acid (CA), which exists in the root of Actinidia chinensis (藤梨), as having a significant anti-cancer effect on HCC cells. We found that CA inhibits VEGFR2 kinase activity by directly interacting with the ATP binding pocket. CA down-regulates the VEGFR2/Src/FAK/cdc42 axis, subsequently decreasing F-actin formation and migratory activity of Huh7 cells in vitro. In an in vivo model, CA exhibites an effective dose (5 mg/kg/day) on tumor growth, and we further demonstrate that CA has a synergistic effect with sorafenib within a wide range of concentrations. In conclusion, we elucidate the effects and molecular mechanism for CA on HCC cells and suggest that CA could serve as a therapeutic or adjuvant target for patients with aggressive HCC. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/4721 |
全文授權: | 同意授權(全球公開) |
顯示於系所單位: | 生物化學暨分子生物學科研究所 |
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