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研究生:辜琮祐
研究生(外文):Chung-Yu Ku
論文名稱: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
論文名稱(外文):Studies on Hepatocellular Carcinoma (HCC):I. Liver Fatty Acid-Binding Protein (L-FABP) Promotes Cellular Angiogenesis and Migration in Hepatocellular CarcinomaII. Corosolic Acid Inhibits Hepatocellular Carcinoma Cell Migration by Targeting the VEGFR2/Src/FAK Pathway
指導教授:林榮耀林榮耀引用關係呂紹俊呂紹俊引用關係
指導教授(外文):Jung-Yaw LinShao-Chun Lu
口試委員:方剛李德章李明學
口試委員(外文):Kang FangTe-Chang LeeMing-Shyue Lee
口試日期:2015-06-24
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:生物化學暨分子生物學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:123
中文關鍵詞: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
外文關鍵詞:Hepatocellular carcinomaangiogenesisliver fatty acid-binding proteinvascular endothelial growth factorcorosolic acidmigrationvascular endothelial growth factor receptor-2 (VEGFR2)
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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.

Abbreviations 1
中文摘要 3
Abstract 5
Introduction
Hepatocellular carcinoma 7
Vascular endothelial growth factor and HCC 7
Liver fatty acid-binding protein (L-FABP) 8
Lipid rafts, receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases 9
Chinese herbal medicines and Actinidia chinensis 10
Corosolic acid (CA) 11
Materials and methods
Part I
Antibodies used for western blot analysis and chemical inhibitors 12
Tissue microarray construction and immunohistochemistry 12
Cell culture 13
Creation and culture of L-FABP overexpressed stable clones 13
Western blot analysis and immunoprecipitation 14
Cell migration assay 14
Angiogenesis activity assay 15
Short interference RNA (siRNA) and short hairpin RNA (shRNA) 16
Lipid rafts isolation 17
Confocal microscopy analysis 18
Small GTPase binding assay 18
Construction of human VEGF-A promoter 19
Luciferase reporter assay 19
Animals 20
Cloning of L-FABP mutants 21
Statistical analysis 21
Part II
Plant extracts 22
HPLC analysis 22
Reagents 22
Cell culture 23
Cytotoxicity assay 23
Migration assay 24
Immunoprecipitation 24
Western blot analysis 25
Kinase activity assay 25
Rho GTPase activity assay 26
G-actin/F-actin activity assay 26
Confocal microscopy analysis 27
Animal model 27
Immunohistochemistry 29
Synergistic analysis 29
Molecular docking 29
SRB cell growth assay 30
Statistical analysis 30
Results
Part I
1. Up-regulation of L-FABP expression in HCC tissues is correlated with VEGF-A
overexpression 31
2. L-FABP induces VEGF-A expression and angiogenic potential in immortalized
Hus and Huh7 cells 31
3. Association of L-FABP with VEGFR2 in membrane rafts 33
4. L-FABP increases VEGFR2/Src phosphorylation and cell migration by
FAK/cdc42 pathway 34
5. L-FABP induced VEGF-A expression by Akt/mTOR/P70S6K/4EBP1 in
translation level 35
6. L-FABP promoted tumor growth and metastasis in vivo 36
7. Cholesterol binding and membrane interacting properties are essential for
L-FABP induced cell migration and angiogenesis 37
Part II
8. Corosolic acid significantly decreases the migration activity of Huh7 cells 38
9. Corosolic acid inhibits VEGFR2 kinase activity 39
10. Corosolic acid decreases cell motility by inhibiting VEGFR2/Src/FAK/cdc42
activity and actin rearrangement 40
11. Corosolic acid exhibits anti-tumor effect in vivo 41
12. Synergistic effects of corosolic acid and sorafenib on HCC cells 42
13. Corosolic acid interacts with the ATP-binding site of VEGFR2 kinase domain
by molecular docking 43
14. Corosolic acid does not exhibit significant inhibitory effects on Huh7 cell 43
Discussion
Part I
Role of L-FABP in hepatocellular carcinoma 45
Part II
Effects of corosolic acid on hepatocellular carcinoma 50
Summary 53
Figures and Figure legend
Part I
Figure 1. Correlation between the expression levels of L-FABP and VEGF-A 54
Figure 2. L-FABP expression is associated with VEGF-A expression of HCC cells 55
Figure 3. Expression level of VEGF-A is up-regulated in L-FABP stably expressed
Hus cells 56
Figure 4. L-FABP promotes in vitro and in vivo angiogenic activity of Hus cells 57
Figure 5. Sequence aliment of L-FABP interacting domains 58
Figure 6. Co- immunoprecipitation of L-FABP and VEGFR2 in Hus/L-FABP cells 59
Figure 7. L-FABP associates with VEGFR2 in apical membrane of Hus/L-FABP
cells 60
Figure 8. Localization of L-FABP and signaling molecules in lipid rafts 61
Figure 9. L-FABP increases the phosphorylation level of VEGFR2 in Hus cells 62
Figure 10. L-FABP increases the phosphorylation level of Src and FAK kinases in
Hus cells 63
Figure 11. L-FABP promotes cdc42 activity of Hus cells 64
Figure 12. Analysis of migration activity of L-FABP stably expressed Hus cells 65
Figure 13. L-FABP up-regulates migration activity through VEGFR2/ Src pathway 66
Figure 14. L-FABP activates Akt/ mTOR/ P70S6K/ 4EBP1 signaling 67
Figure 15. HIF-1α significantly enriched in the nucleus of L-FABP overexpressed
cells 68
Figure 16. Role of HIF-1α in VEGF-A transcriptional activity of L-FABP
overexpressed cells 69
Figure 17. Post-transcriptional regulation of VEGF-A in L-FABP stably expressed
Hus cells 70
Figure 18. L-FABP promotes tumor growth in vivo 71
Figure 19. L-FABP promotes in vivo metastasis by lung metastasis model 72
Figure 20. Effect of L-FABP mutants in VEGF-A expression 73
Figure 21. Effect of L-FABP mutants in migration activity 74
Figure 22. Cholesterol binding properties are essential for L-FABP induced cell
migration and angiogenesis 75
Figure 23. Knockdown of L-FABP in Hus/L-FABP cells reversely decreased
VEGF-A expression and migration activity 76
Figure 24. Knockdown of L-FABP in Huh7 cells down-regulates VEGF-A
expression and migration activity 77
Figure 25. Reduction of L-FABP and VEGFR2 co-localization on membrane is
observed in Huh7 L-FABP stably knockdown cells 79
Figure 26. Aberrant overexpression of L-FABP in HCC tissues (with cirrhosis) is
associated with worse outcome 80
Part II
Figure 27. Cytotoxicity and migration inhibitory effect of Actinidia chinensis on
Huh7 cells 81
Figure 28. HPLC analysis of Actinidia chinensis 82
Figure 29. Migration activity of Huh7 cells is inhibited by corosolic acid without
cytotoxicity 83
Figure 30. Corosolic acid reduces phosphorylation level of VEGFR2 84
Figure 31. Corosolic acid reduces VEGFR2 kinase activity 85
Figure 32. CA-induced inhibition of migration activity in Huh7 cells is VEGFR2
dependent 86
Figure 33. Corosolic acid down-regulates VEGFR2 downstream signals 87
Figure 34. Corosolic acid inhibits cdc42 activity 88
Figure 35. Effect of corosolic acid on actin rearrangement 89
Figure 36. Corosolic acid exhibits significant anti-tumor effects on Huh7 cells in
vivo 90
Figure 37. Combinatorial effects of corosolic acid and sorafenib on migration
activity of Huh7 cells 92
Figure 38. Combinatorial effects of corosolic acid and sorafenib on signaling
molecules of Huh7 cells 93
Figure 39. Combinatorial effects of corosolic acid and sorafenib on Huh7 cells by 94
in vivo xenograft model
Figure 40. Inhibitory effects of corosolic acid combined with sorafenib on Src and
FAK kinases in vivo
95
Figure 41. Corosolic acid interacts with the ATP-binding site of VEGFR2 kinase
domain by molecular docking analysis
96
Figure 42. Analysis of relative distance and surface charge distribution between
corosolic acid and VEGFR2 ATP binding pocket
97
Figure 43. Corosolic acid inhibits growth of Huh7, HepG2, and Hep3B cells 98
Figure 44. Cytotoxicity and migration-inhibitory effects of corosolic acid on
HepG2 cells
99
Figure 45. Cytotoxicity and migration-inhibitory effects of corosolic acid on
Hep3B cells
100
Figure 46. Corosolic acid doesn’t exhibit significant inhibitory effect on invasion
activity of Huh7 cells
101
Figure 47. Corosolic acid shows no inhibitory effect on NFκB signaling 102
Tables
Table 1. Correlation between L-FABP and VEGF-A protein expression in tissue
pairs from 90 HCC patients 103
Table 2. Clinical characteristics of the cases included in analyses of L-FABP
protein expression evaluated by immunohistochemistry 103
Table 3. Association of L-FABP protein expression with clinical pathologic
characteristics in patients with HCC 104
Supplementary data
Table 1 105
Figure 1. Knockdown of VEGFR2 in Hus/L-FABP cells decreased the activation
of down-stream signaling molecules 107
Figure 2. Prediction of the interaction models of L-FABP and VEGFR2 kinase
domain 108
Figure 3. Amino acid substitution of L-FABP in present studies 109
References 110

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