Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/90150
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dc.contributor顏國欽zh_TW
dc.contributorGow-Chin Yenen_US
dc.contributor.author張珩毓zh_TW
dc.contributor.authorHeng-Yu Changen_US
dc.contributor.other食品暨應用生物科技學系所zh_TW
dc.date2014zh_TW
dc.date.accessioned2015-12-09T03:06:28Z-
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dc.identifier.urihttp://hdl.handle.net/11455/90150-
dc.description.abstractProstate cancer is the first cause of male cancer incidence in the developed countries and is hard to eradicate because of the high metastasis and easy relapse. Therefore, the prevention and therapy of prostate cancer is an important study. Tumor with rapid growth is one of the characteristics in cancer metastasis, resulting from growing environments of hypoxia, starvation and chronic inflammation within the tumor tissue. The stress stimulation during harsh environment not only causes to get nutrients and growing space but also to invade surrounding tissue into the circulatory system. Epithelial-mesenchymal transition (EMT) is the first step in the process of cancer cells with invasion and tumor metastasis, which can help cell adhesion decrease the ability of cell-cell junction and generate cell polarity. The effects result in tumor escape form tumor tissue and migrate, eventually leading to invasion and metastasis. HMGB1plays a role of non-histone chromatin binding nuclear protein and a damage-associated molecular pattern (DAMP), which is released to extracellular by active and passive modes during cell damage. Thus, cancer cells can resist environmental stimuli and injury. The aim of this study was to investigate whether HMGB1 expression can affect its release and regulatory ability of EMT to cause cell invasion. In addition, we also explored the reversal potential effect of phytochemical glycyrrhizin (GR) on E-cadherin of prostate cancer cells was also explored. The results indicated that knockdown of HMGB1 reduced HMGB1 release in prostate cancer cells, leading to inhibition of phosphorylation of Rac1/Cdc42 to promote GSK-3β activity. The level of GSK-3β activation induced snail degradation and reduced its translocation which increased E-cadherin expression and promoted cell adhesion to down-regulate cell polarity and reduce tumor metastasis. In addition to directly regulate E-cadherin expression, HMGB1 was inhibited to indirectly regulate EMT before being reduced EMT relative inflammatory factor release such as IL-6 and IL-8 to avoid a better condition beneficial for tumor metastasis. To further investigated whether HMGB1-induced Rac1/cdc42 signaling is a major regulatory pathway regarding modulation of EMT ability in prostate cancer cells. The serum-free medium was applied to simulate a starvation environment in tumor growth. The results showed that low expression of HMGB1 in prostate cancer cells exhibited poor ability of tumor migration and low expression of EMT-related inflammatory factors. Based on these finding, HMGB1 is a critical EMT regulator. GR is one of the sweet substances in Liquorice. The recent reports showed that GR is able to bind with HMGB1 to inhibit its cytokine activity. We also found that GR suppressed tumor migration and recovered E-cadherin expression in prostate cancer cells. In conclusion, HMGB1 could be a hallmark to tumor metastasis. Reduction of prostate cancer metastasis occurred through suppression of HMGB1 releasing and recovering. GR is a phytochemical and has capability to bind HMGB1 and to inhibit tumor metastasis. Therefore, it is suggested that GR may have potential of adjuvant chemotherapy and as an adjuvant therapy.en_US
dc.description.abstract攝護腺癌於已開發國家男性癌症罹患率位居首位,具有高度轉移性且易復發,導致難以根治,因此攝護腺癌之預防及治療為相當重要之研究。癌細胞轉移主因來自於快速生長之特性,導致腫瘤組織內部呈現缺氧、飢餓及慢性發炎之生長環境,癌細胞由於惡劣環境壓力刺激而導致其為了獲得更多養分及生長空間,侵入到周遭組織並進入循環系統。上皮間質轉化現象 (epithelial-mesenchymal transition, EMT)之過程為癌細胞具有侵入轉移之首要步驟,此步驟幫助癌細胞減弱細胞與細胞間黏附能力,並產生細胞極性,使癌細胞脫離腫瘤組織並具有移行能力,進而促進侵入轉移進行。HMGB1 (High mobility groupbox-1) 為一種核蛋白,正常情況下扮演非組蛋白染色質結合蛋白(non-histone chromatin binding protein)之角色,然而細胞受到傷害或刺激之情況下會透過主動及被動兩種方式釋放至細胞外,作為損傷相關分子 (damage-associated molecular pattern, DAMP),幫助細胞抵抗外來環境之刺激及傷害。本研究目的為探討 HMGB1 於 DU 145 攝護腺癌細胞表現之差異是否會影響其釋放及調控其 EMT 能力 進而調,控癌細胞侵入轉移之特性,並探討天然植物化合物甘草甜素(Glycyrrhizin, GR)回復癌細胞 E-cadherin 表現之潛力。 本研究結果指出,利用基因弱化 (Knockdown) 方式降低攝護腺癌細胞中 HMGB1 (High-mobility group box-1)表現量確實顯著減弱HMGB1 之釋放,此結果導致癌細胞之 Rac1/Cdc42 磷酸化表現減弱,而促進癌細胞 GSK-3β 活性,導致 snail 之降解並減少其轉位,而促使 E-cadherin 表現量顯著提升,進而增加癌細胞間黏附能力,導致癌細胞移行能力減弱而達到抑制侵入轉移之能力。Rac1/Cdc42 之活化除了降低 E-cadherin 外,也可降低癌細胞極性 (cell polarity) 之形成,而使細胞無法脫離腫瘤組織進行移動。除了直接調控訊息傳遞路經促使癌細胞 EMT 能力上升外,抑制 HMGB1 也可減少 EMT 相關發炎因子 IL-6 及 IL-8 之表現量,而避免癌細胞處於有利於侵入轉移之微環境。 此外,以無血清環境方式模擬攝護腺癌細胞處於飢餓環境,進一步探討是否於惡劣生長環境下,HMGB1 所誘導之 Rac1/Cdc42 路徑之活化仍是調控癌細胞 EMT 能力之主要訊息傳遞路徑 結果顯示,。在無血清環境下,HMGB1 釋放確實具有活化前述訊息傳遞路徑之能力,並且經由基因弱化而導致 HMGB1 表現量較低之攝護腺癌細胞株 在無血清環境下之移行能力顯著降低 由此數據顯示 HMGB1 在,,癌細胞 EMT 能力之調控扮演重要之角色 甘草中之主要甜味物質為。甘草甜素,近期文獻指出甘草甜素具有補捉 HMGB1 而抑制其細胞激素功能之用途。本研究發現介入甘草甜素能有效抑制攝護腺癌細胞移 行 之 能 力 , 並 回 復 正 常 HMGB1 表 現 量 之 攝 護 腺 癌 細 胞E-cadherin 表現量。 綜合上述結果 HMGB1 確實可作為癌症侵入轉移能力之指標,,抑制 HMGB1 之釋放或捕捉已釋放 HMGB1 具有抑制攝護腺癌細胞侵入轉移之功能性。天然植物化合物中,甘草甜素可透過螯合HMGB1 而回復攝護腺癌 E-cadherin 表現量,進而降低癌細胞之侵入轉移能力,因此推測甘草甜素具有輔助治療及作為化療藥物佐劑之潛力。zh_TW
dc.description.tableofcontents中文摘要..........i 英文摘要..........iii 圖次..........ix 附圖..........xii 縮寫表.......... xiii 前言..........1 壹、文獻整理 ..........3 一、攝護腺癌 (prostate cancer) 簡介 ..........4 二、癌症(cancer)與侵入轉移(invasion and metastasis)之簡介 ..........4 三、Epithelail-mesenchymal transition (EMT) 簡介..........5 1. EMT 與侵入 (invasion) 及轉移 (metastasis) 之關係..........5 2. E-cadherin 降解 ..........6 3. EMT 與細胞極性 (cell polarity) ..........6 4. EMT 調控之訊息傳遞 ..........7 四、High-mobility group protein B1(HMGB1)簡介..........21 1. HMGB1 功能 ..........21 2. The receptor for advanced glycation end products (RAGE) ......22 3. RAGE 與 HMGB1 ..........23 4. HMGB1 與癌症..........24 5. 攝護腺癌之 HMGB1 與 RAGE 之臨床研究..........27 6. 以 HMGB1 作為標的於癌症治療之應用..........28 五、甘草..........29 貳、研究目的 ..........37 HMGB1 對於攝護腺癌細胞上皮間質轉化過程之調控及甘草甜素回復 E-cadherin 之潛力 ..........39 ?、研究架構 ..........40 肆、材料與方法 ..........41 一、實驗材料 ..........41 1. 細胞株 ..........41 2. 藥品 ..........41 二、實驗方法..........42 1. 細胞培養..........42 2. 細胞繼代與冷凍保存 (貼附型) ..........43 3. 細胞存活率測定 (MTSassay) ..........43 4. 傷口癒合試驗 (wound healing) ..........43 5. 細胞移行試驗 (Transwell assay) ..........44 6. 細胞內 RNA 抽取..........44 7. 合成 cDNA ..........45 8. Polymerase Chain Reaction (PCR) 反應..........45 9. 瓊脂膠體電泳 ..........46 10. 蛋白質之萃取 (貼附型細胞) ..........46 11. 細胞核/細胞質蛋白質之萃取 (貼附型細胞) ..........46 12. 培養基中 HMGB1 蛋白質濃縮 ..........47 13. 聚丙烯醯胺膠體電泳法 (SDS-PAGE) 分析..........47 14. 西方轉漬法 (Western blot assay..........48 15. 螢光免疫染色法 (Immunofluorescencev48 16. 酵素連結免疫吸附測定分析(Enzyme-linked immunosorbent assay, ELISA) ..........49 17. 胞內鈣離子濃度 ..........49 18. 統計分析 ..........50 伍、結果..........51 一、攝護腺癌細胞中 HMGB1 基因弱化 (Knockdown) 細胞株篩選.... 51 1. DU145 及 PC3 攝護腺癌細胞株 HMGB1 基因弱化結果........51 2. DU145 攝護腺癌細胞株之 HMGB1 基因弱化穩定性 ...........51 二、HMGB1 表現量對於攝護腺癌之 EMT 能力相關特性之探討 .52 1. HMGB1 基因弱化對於攝護腺癌中 HMGB1 釋放之調控 .....52 2. HMGB1 表現量對於攝護腺癌胞內鈣離子濃度之調控 ...........52 3. HMGB1 表現量對於攝護腺癌細胞 NF-κB 訊息傳遞路徑之調控 .... 52 4.Ethyl pyruvate 對 HMGB1 誘導之 DU145 細胞移性之影響 ....53 5.HMGB1 表現量對於攝護腺癌細胞在 poly-HEMA 處理環境下黏附能力影響 ..........53 6. HMGB1 表現量對攝護腺癌細胞在 E-cadherin 及 vimintin 表現調控之影響..........54 7. HMGB1 表現量對於攝護腺癌細胞之 E-cadherin 與 vinmintin螢光表現之影響..........54 8. HMGB1 表現量對於攝護腺癌細胞 snail 轉位活性之調控......55 9.HMGB1 表現量對於攝護腺癌細胞 GSK-3β 磷酸化調控之影響..... 55 10. HMGB1 表現量對於攝護腺癌細胞之 snail 表現量之調控..56 11. HMGB1 表現量差異對於攝護腺癌 snail 穩定性及 E-cadherin表現量間之調控..... 56 12. HMGB1 經 PI3K 及 MAPK 訊息傳遞路徑調控攝護腺癌細胞 EMT 之影響 ...... 57 13. HMGB1 表現量調控攝護腺癌細胞 TGF-β 之表現量。 .......57 14. HMGB1 經 Rac1/cdc42 訊息傳遞路徑調控攝護腺癌細胞 EMT之影響 ..... 58 15. HMGB1 表現調控攝護腺癌細胞 EMT 相關發炎因子之表現量........ 58 三、HMGB1 表現對於攝護腺癌於無血清環境下對 EMT 能力相關特性之探討 ...... 59 1. 無血清環境下 HMGB1 對於攝護腺癌細胞 E-cadherin 及β-catenin 基因表現之調控..........59 2. HMGB1 基因弱化對於攝護腺癌在無血清環境下 HMGB1 釋放之調控 ...... 59 3. HMGB1 表現量對於攝護腺癌細胞在低血清誘導下移行能力之影響 ...... 60 4. HMGB1 表現量對於攝護腺癌細胞在無血清移行能力之影響 60 5. HMGB1 表現量對攝護腺癌細胞在無血清環境下 E-cadherin與 vimintin 表現量之調控 ........ 61 6. HMGB1 表現量對攝護腺癌細胞在無血清環境下 snail 轉位活性之調控 ..... 61 7. HMGB1 表現對於攝護腺癌細胞在無血清環境下 Rac1/Cdc42 -GSK-3β 訊息傳遞路徑之調控 ..........62 8. HMGB1 表現量於無血清環境下調控攝護腺癌細胞 EMT 相關發炎因子之表現量..........62 四、甘草甜素介入對於攝護腺癌細胞 EMT 能力之影響 ..........63 1. 甘草甜素對 DU145 parental 及 DU145 HMGB1-L 攝護腺癌細胞之細胞毒性影響..........63 2. 甘草甜素對不同 HMGB1 表現量之攝護腺癌細胞 E-cadherin表現量之影響....63 3. 甘草甜素對不同 HMGB1 表現量之攝護腺癌細胞移行能力之影響..........63 陸、討論..........65 柒、結論..........76 參考文獻..........107zh_TW
dc.language.isozh_TWzh_TW
dc.rights不同意授權瀏覽/列印電子全文服務zh_TW
dc.subjectHMGB1en_US
dc.subjectDU145prostate cancer cell,epithelial-mesenchymal transitionen_US
dc.subjectRac1/Cdc42, GSK-3βen_US
dc.subjectcell polarityen_US
dc.subjectE-cadherin, glycyrrhizinen_US
dc.subjectHMGB1zh_TW
dc.subjectDU145 攝護腺癌細胞zh_TW
dc.subject上皮間質轉化現象zh_TW
dc.subjectRac1/Cdc42zh_TW
dc.subjectGSK-3βzh_TW
dc.subject細胞極性zh_TW
dc.subjectE-cadherinzh_TW
dc.subject甘草甜素zh_TW
dc.titleHMGB1 對於攝護腺癌細胞上皮間質轉化過程之調控及甘草甜素回復 E-cadherin 之潛力zh_TW
dc.titleRegulatory effect of HMGB1 on the process of epithelial-mesenchymal transitionand reversal potential role of glycyrrhizin on E-cadherin in prostate cancer cellsen_US
dc.typeThesis and Dissertationen_US
dc.date.paperformatopenaccess2018-07-15zh_TW
dc.date.openaccess10000-01-01-
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