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dc.contributorMiao-Lin Huen_US
dc.contributor.authorBo-Yi Jhouen_US
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dc.description.abstractNADPH 氧化酶 4 (NADPH oxidase 4, NOX4)具有產生活性氧(reactive oxygenspecies, ROS)的功能,且與癌細胞轉移呈正相關。臨床研究已經指出,相對於使用抗氧化劑療法,針對能產生 ROS 的酵素作為標靶對於治療由過量 ROS 所引起的癌症可能是較好的方法。先前研究發現,在人類肝癌細胞株 SK-Hep-1 中,蕃茄紅素具有降低 ROS 的生成以及抑制癌細胞轉移的能力。然而,NOX4 在蕃茄紅素的抗癌轉移作用中所扮演的角色目前仍不清楚。在本篇研究中,我們首先驗證了本研究室先前的結果,亦即:蕃茄紅素(0.1-5 μM)與 SK-Hep-1 細胞培養 2-12小時後,可顯著地抑制細胞移行、侵襲以及黏附的能力;在培養 24 小時後,可顯著地抑制細胞基質金屬蛋白酶(matrix metalloproteinase, MMP)-9 和-2 的酵素活性;在培養 0.5-6 小時後,可顯著地降低細胞內 ROS 的產生。我們也首次發現,蕃茄紅素(0.1-5 μM)與 SK-Hep-1 細胞培養 2 小時後,可顯著地抑制 NOX4 的蛋白質表現及 NADPH 氧化酶活性,以及抑制 mothers against decapentaplegic 2/3(SMAD2/3)的蛋白質表現。接著,我們使用 NOX4 之非特異性抑制劑diphenyleneiodonium (DPI)與蕃茄紅素合併培養細胞,以確認 NOX4 在蕃茄紅素的抗癌轉移作用中所扮演的角色。結果顯示,合併使用低濃度的 DPI 與蕃茄紅素對於細胞的移行能力 MMP-9 和 MMP-2 的酵素活性以及 NADPH 氧化酶活性、具有更強的抑制效果,意味著 NOX4 可能參與了蕃茄紅素的抗癌轉移作用。我們更進一步地探討蕃茄紅素對於由轉化生長因子(transforming growth factor-β,TGF-β)所誘發之癌轉移所造成的影響,以確認 NOX4 在蕃茄紅素所調節的癌轉移中所扮演的角色。結果顯示 TGF-β (5 ng/mL)可顯著地促進細胞移行、侵襲及黏附能力,並且增加細胞內 ROS 生成、促進 MMP-9 及 MMP-2 酵素活性、促進NOX4 的蛋白質表現、NADPH 氧化酶活性,以及促進 SMAD2/3 的蛋白質表現。當細胞與 TGF-β 及蕃茄紅素(2.5 μM)兩者合併培養之後 這些由 TGF-β 所造成的,改變則可以被蕃茄紅素所逆轉。最後,我們將 SK-Hep-1 細胞中 NOX4 表現利用短暫性轉染 siRNA 使其靜默化,結果發現,相對於沒有將 NOX4 基因靜默化的控制組,NOX4 基因靜默化後可以完全抵消蕃茄紅素、TGF-β 以及兩者合併使用對於細胞移行能力、NOX4 和 SMAD2/3 蛋白質表現的影響,並且削弱 MMP-9和 MMP-2 的酵素活性。以上結果說明,TGF-β 所誘發之 NOX4-ROS-SMAD2/3訊息傳遞路徑參與了蕃茄紅素抑制人類肝癌細胞株 SK-Hep-1 癌轉移的作用。zh_TW
dc.description.abstractNADPH oxidase 4 (NOX4) with the sole function to produce reactive oxygen species (ROS) has been shown to be positively associated with cancer metastasis. Clinical studies have indicated that, relative to antioxidant therapy, targeting ROS-producing enzymes may be a more beneficial strategy to combat cancers caused by excess ROS. Lycopene has been shown to attenuate ROS production and inhibit tumor metastasis in human hepatocarcinoma SK-Hep-1 cells. However, the role of NOX4 in the anti-metastatic action of lycopene remains unknown. Herein, we first confirmed the inhibitory effect of lycopene on the metastasis in SK-Hep-1 cells by showing that treatment of lycopene (0.1-5 μM) significantly inhibited migration, invasion and adhesion at 2-12 h of incubation, suppressed activities of matrix metalloproteinase (MMP)-9, -2 at 24 h of incubation, and decreased intracellular ROS production at 0.5-6 h of incubation. We found for the first time that lycopene (0.1-5 μM) significantly inhibited NOX4 protein expression, NADPH oxidase activity, and mothers against decapentaplegic 2/3 (SMAD2/3) protein expression at 2 h of incubation. We then used diphenyleneiodonium (DPI), the most widely used NOX4 non-specific inhibitor, in combination with lycopene to confirm the role of NOX4 in the anti-metastatic actions of lycopene. Results reveal that relative low levels of DPI in combination with lycopene exhibited stronger inhibition of migration, MMP-9 and MMP-2 activities, and NADPH oxidase activity, suggesting that NOX4 may be involved in the anti-metastatic effects of lycopene. We further determined the effects of lycopene on transforming growth factor β (TGF-β)-induced metastasis to confirm the role of NOX4 on lycopene-mediated cancer metastasis. Results reveal that TGF-β (5 ng/mL) significantly increased migration, invasion, adhesion, intracellular ROS production, MMP-9 and MMP-2 activities, NOX4 protein expression, NADPH oxidase activity and SMAD2/3 protein expression. These changes caused by TGF-βwere completely reversed by pre-incubation of SK-Hep-1 cells with lycopene (2.5 μM). Using transient transfection of siRNA against NOX4, we found that NOX4 knockdown completely abolished the effects of lycopene, TGF-β and the combined treatment on migration, NOX4 and SMAD2/3 protein expression as well as partially decreased activities of MMP-9 and MMP-2, as compared to non-silencing group. Overall, the present results demonstrate that the NOX4-ROS-SMAD2/3 pathway that is known to be induced by TGF-β is involved in the anti-metastatic action of lycopene in human hepatocarcinoma SK-Hep-1 cells.en_US
dc.description.tableofcontents謝誌.......... I 中文摘要.......... II Abstract.......... IV Table of contents.......... VI List of figures.......... X List of abbreviations.......... XII 1. Literature Review..........1 1.1 Hepatocellular carcinoma (HCC) ..........2 1.2. Tumor metastasis...........2 1.3. Biomolecules of metastasis..........3 1.3.1 Matrix metalloproteinases (MMPs) ..........3 1.3.2 Reactive oxygen species (ROS) ..........4 1.3.3 Transforming growth factor (TGF) ..........4 1.3.4 Mothers against decapentaplegic (SMAD) ..........5 1.3.5 Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) ..........6 1.4. Carotenoids..........7 1.5. Lycopene..........7 1.6. Biological functions of lycopene..........8 1.6.1 Cell culture studies..........9 Anti-proliferation..........9 Cell cycle arrest..........9 Induction of cell apoptosis..........10 Enhancement of gap junctional intercellular communication (GJIC)..........11 Cholesterol efflux and synthesis..........12 Anti-metastasis..........12 Anti-angiogenesis..........13 1.6.2 Animal studies..........14 Tumor xenografted models..........14 Lung metastasis model...........15 Chemicals-induced carcinogenesis models..........15 Angiogenesis model..........16 1.6.3 Human studies..........16 Epidemiological studies..........16 1.6.3. 2 Clinical trials..........17 1.7. Motivation, specific aims and hypothesis..........18 1.7.1 Motivation..........18 1.7.2 Specific aims..........18 1.7.3 Hypothesis..........18 1.8. Experimental scheme..........19 2. Materials and Methods..........20 2.1 Materials..........21 2.2 Lycopene preparation..........21 2.3 Cell culture..........22 2.4 Cell migration and invasion assay..........22 2.5 Cell adhesion assay..........23 2.6 Determination of intracellular ROS levels..........23 2.7 Analysis of NADPH oxidase activity..........24 2.8 Gelatin zymography.......... 24 2.9 Western blotting.......... 25 2.10 Transient transfection of siRNA against NOX4.......... 25 2.11 Statistical analysis..........26 3. Results..........27 3.1 Effects of lycopene on cancer metastasis in SK-Hep-1 cells..........28 3.1.1 Lycopene inhibited migration, invasion and adhesion in SK-Hep-1 cells..........28 3.1.2 Lycopene inhibited activities of MMP-9 and MMP-2 in culture medium of SK-Hep-1 cells.......... 28 3.1.3 Lycopene decreased intracellular ROS production in SK-Hep-1 cells..........29 3.1.4 Lycopene inhibited NOX4 protein expression and NADPH oxidase activity in SK-Hep-1 cells..........29 3.1.5 Lycopene inhibited SMAD2/3 protein expression in SK-Hep-1 cells..........30 3.2 Effects of lycopene in combination with DPI on cancer metastasis in SK-Hep-1cells..........30 3.2.1 DPI alone or in combination with lycopene inhibited migration in SK-Hep-1 cells…..30 3.2.2 DPI alone or in combination with lycopene inhibited MMP-9 and MMP-2 activities in culture medium of SK-Hep-1 cells.......... 31 3.2.3 DPI alone or in combination with lycopene decreased NADPH oxidase activity in SK-Hep-1 cells..........31 3.3 Effects of lycopene on TGF-β-induced cancer metastasis in SK-Hep-1 cells…...32 3.3.1 Lycopene reversed TGF-β-induced migration, invasion and adhesion in SK-Hep-1 cells..........32 3.3.2 Lycopene reversed TGF-β-induced intracellular ROS production in SK-Hep-1 cells…32 3.3.3 Lycopene reversed TGF-β-induced MMP-9 and MMP-2 activities in culture medium of SK-Hep-1 cells..........33 3.3.4 Lycopene reversed TGF-β-induced NOX4 protein expression and NADPH oxidase activity in SK-Hep-1 cells..........33 3.3.5 Lycopene reversed TGF-β-induced SMAD2/3 protein expression in SK-Hep-1 cells...34 3.4 TGF-β-NOX4-SMAD2/3 pathway involved the anti-metastatic effects of lycopene in SK-Hep-1 cells..........34 3.4.1 Effects of NOX4 knockdown on lycopene-mediated TGF-β-induced NOX4 protein expression in SK-Hep-1 cells..........34 3.4.2 Effects of NOX4 knockdown on lycopene-mediated TGF-β-induced migration in SK-Hep-1 cells..........34 3.4.3 Effects of NOX4 knockdown on lycopene-mediated TGF-β-induced MMP-2 and MMP-9 activities in culture medium of SK-Hep-1 cells.......... 35 3.4.4 Effects of NOX4 knockdown on lycopene-mediated TGF-β-induced SMAD2/3 protein expression in SK-Hep-1 cells.......... 35 4. Discussion..........36 5. References.......... 66zh_TW
dc.subjectNADPH oxidase 4en_US
dc.subjectSK-Hep-1 cellsen_US
dc.subjectNADPH 氧化酶 4zh_TW
dc.titleRole of lycopene in NADPH oxidase 4-mediated metastasis in human hepatocarcinoma SK-Hep-1 cellsen_US
dc.title蕃茄紅素在人類肝癌細胞 SK-Hep-1 中對於NADPH 氧化酶 4 調節之癌細胞轉移所扮演的角色zh_TW
dc.typeThesis and Dissertationen_US
item.openairetypeThesis and Dissertation-
item.fulltextwith fulltext-
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