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研究生:林佳宏
研究生(外文):Lin, Chia-Hung
論文名稱:黃酮類化合物和舞菇水萃取物的抗癌潛力
論文名稱(外文):The anticancer effects of flavonoids and Grifola frondosa water extract
指導教授:李寬容李寬容引用關係
指導教授(外文):Lee, Kuan-Rong
口試委員:萬磊林振文林雲冰陳煥源
口試委員(外文):Wan, LeiLin, Cheng-WenLin, Yun-PingChen, Huan-Yuan
口試日期:2017-03-28
學位類別:博士
校院名稱:國立清華大學
系所名稱:分子醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:英文
論文頁數:149
中文關鍵詞:乳癌細胞凋亡黃酮舞菇肝癌細胞自嗜
外文關鍵詞:BreastcancerApoptosisFlavonesGrifola frondosaHepatocellular carcinomaAutophagy
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癌症是全世界主要的公共衛生問題,世界衛生組織(WHO)研究指出全世界的癌症都在不斷的上升。報告中指出亞州已經成為癌症發生率和死亡率第一的地區。1971年美國政府成立了國家癌症法案,投注了超過100萬美元的金額希望能找到治癒癌症的方法,卻沒有十分有效的成果。中草藥於數百或者數千年的中國就被廣泛的使用。有大量的證據顯示中草藥具有治療疾病的效果,但是沒有人知道真正的原理。目前全世界都在關注中草藥的研究,希望藉由科學的方式找到對抗癌症的新契機。在此同時有越來越多的研究顯示中草藥的化合物在預防腫瘤的發生以及抑制腫瘤的生長具有很大的潛力。第一個研究主題是探討中草藥萃取出的類黃酮化合物對於預防和治療乳癌的可能方法及其他們的分子機轉。乳癌在台灣是一個重要的公共衛生問題。近幾年來乳癌在台灣癌症發生率和死亡率逐漸的升高。相較於歐美國家,台灣女性好發率比歐美國家早,因此找尋可幫助我們在乳癌的預防及治療的方法就顯得重要。類黃酮為水溶性物質,被發現在中草藥中,目前已知它具有抗過敏、抗發炎、抗病毒、抗氧化和抗腫瘤等這些生物活性。在我們的研究中發現利用MTT細胞存活實驗的結果顯示類黃酮化合物對於人類乳癌細胞HS578T,MDA-MB-231和MCF-7的生長具有抑制的效果。透過Hoechst33342染色和細胞週期的亞G1期的誘導來證實黃酮,芹菜素和木犀草素誘導凋亡抑制乳腺癌細胞生長的能力。另外乳癌細胞處理黃酮,芹菜素和木犀草素會透過抑制PI3K/AKT來誘導FOXO3a蛋白的表達。 包括細胞週期和細胞凋亡相關蛋白p21,p27 ,PARP和Cytochrome c的水平。
第二個研究的主題則是探討舞菇冷水萃取物及其活性部分對抗肝癌的能力以及其分子機制。蘑菇是中國傳統的中醫治療藥物。我們已經知道,蘑菇,可以治療多種疾病。特別是,舞菇一個主要的抗腫瘤生物活性,一直是科學和臨床研究的主要目標。舞菇在許多亞洲國家都有,其特徵在於,子實體肉質,有柄,多分枝,末端形成菌蓋,重疊呈叢。肝癌早期無任何的症狀,發現時通常已經是晚期了。這也是肝癌容易致死的原因。由於到目前為止還沒有一個成功的化療藥物可以使用,所以找尋新的化療藥物是非常重要的。本研究的目的是調查舞菇在肝癌細胞Hep3B的預防作用。最近的研究表明,舞菇通過誘導細胞凋亡來抑制腫瘤的生長。然而,我們仍不知道舞菇誘導的細胞凋亡是否透過其他機制,如自噬。在這裡,我們發現,舞菇的水萃取物,可以通過抑制PI3K/AKT和ERK訊息路徑並且活化人類Hep3B癌細胞的caspases而誘導細胞自噬和死凋亡。在這項研究中,我們將舞菇的水萃取物15.6或7.8微克/毫升,處理在Hep3Be肝癌細胞中,之後我們發現Hep3B肝癌細胞分別顯著的減少95%和90%的數量。另外發現Hep3B肝癌細胞處理舞菇的水萃取物會增加自噬相關蛋白LC3-A,LC3B,ATG3,ATG5,ATG7和Beclin-1的表現量。Hep3B肝癌細胞處理舞菇的水萃取物會導致自噬和細胞凋亡相關的訊息路徑如磷酸化的PI3K(Tyr485/Tyr199),AKT(Ser473的),ERK(Thr202/Tyr204)表現量下降,然後往下調節Bcl-2蛋白,活化caspase-3和caspase-9和PARP。我們還證明,舞菇的水萃取物對Hep3B肝癌細胞移植在裸鼠體產生的腫瘤具有抑制腫瘤生長的能力。我們的結果證明,舞菇的水萃取物抑制Hep3B肝癌細胞的死亡是透過誘導自噬和細胞凋亡所造成的。
Cancer is the world's major public health problem. World Health Organization (WHO) study pointed out that the world's cancer is constantly rising. The report pointed out that Asia has become the first incidence of cancer and mortality areas. In 1971 the US government set up a national cancer bill. They bet more than $ 1 million in the amount of hope to find a cure for cancer, but not very effective results. Chinese herbal medicine is widely used in hundreds or thousands of years. There is lot of evidence that Chinese herbal medicine has the effect of treating the disease. At present the world is in the study of Chinese herbal medicine. Scientists hope to find a new way of anti-cancer by science. At the same time, more and more studies have shown that Chinese herbal compounds have great potential to prevent tumor and inhibit tumor growth. In the first study is to evaluate the extraction of flavonoids from Chinese herbal medicine for the prevention and treatment of breast cancer and their molecular mechanisms. Flavone, apigenin and luteolin showed potent inhibitory effects on the proliferation of Hs578T, MDA-MB-231 and MCF-7 breast cancer cells in a concentration and time-dependent manner. The ability of flavone, apigenin and luteolin to inhibit the growth of breast cancer cells through apoptosis was confirmed by Hoechst33342 staining and the induction of sub-G1 phase of the cell cycle. Flavone, apigenin and luteolin induced forkhead box O3 (FOXO3a) expression by inhibiting Phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB)/Akt. This subsequently elevated the expression of FOXO3a target genes, including the Cyclin-dependent kinase inhibitors p21Cip1 (p21) and p27kip1 (p27), which increased the levels of activated poly(ADP) polymerase (PARP) and cytochrome c.
In the second study is to evaluate Grifola frondosa (GF) cold-water extract and its active part of the ability to effect on hepatocellular carcinoma and its molecular mechanisms. Mushrooms are used in traditional Chinese medicine to treat a variety of diseases. GF is an edible mushroom indigenous to many Asian countries with a large fruiting body characterized by overlapping caps. In particular, GF is known for its anti-tumor activity, which has been targeted by scientific and clinical research. This study aimed to investigate the effects of the cold-water extract of GF (GFW) and its active fraction (GFW-GF) on autophagy and apoptosis, and the underlying mechanisms in vitro and in vivo. Our results revealed that GFW and GFW-GF inhibited phosphatidylinositol 3-kinase (PI3K) and stimulated c-Jun N-terminal kinase (JNK) pathways, thereby inducing autophagy. We also demonstrated that GFW and GFW-GF inhibited proliferation, induced cell cycle arrest, and apoptosis in Hep3B hepatoma cells. GFW and GFW-GF markedly arrested cells in S phase and promoted cleavage of caspase-3 and -9. In addition, GFW and GFW-GF decreased the expression levels of the anti-apoptotic proteins protein kinase B and extracellular signal-regulated kinase. We also found that GFW significantly inhibited tumor growth in nude mice implanted with Hep3B cells. Our work demonstrates that GF and its active fraction inhibit hepatoma growth by inducing autophagy and apoptosis.
中文摘要
Abstract
致謝
Chapter 1: Introduction …………………………….. 1-5
(i) Flavonoids
(ii) Grifola frondosa
(iii) The relationship between Chinese herbal medicine and cancer
Chapter 2:
Title of article: Flavone inhibit breast cancer proliferation through the Akt/FOXO3a signaling pathway

2.1 Abstract…………………………………………….............. 6-6
2.2 Introduction ……………………………………………….. 8-11
2.3 Material and Methods …………………………………......12-18
2.3.1 Cell lines and cell culture
2.3.2 Cell viability assay
2.3.3 Hoechst 33342 staining for detection of cell apoptosis
2.3.4 Cell cycle analysis
2.3.5 Colony formation assay
2.3.6 Wound healing assay
2.3.7 Analysis of cell migration and invasion
2.3.8 RNA extraction, reverse transcription (RT), and real-time PCR
2.3.9 Western blot
2.3.10 Statistical analysis
2.4 Results …………………………………………………….. 19-24
2.4.1 Effects of flavone, apigenin and luteolin on cell viability and apoptosis of breast cancer cells
2.4.2 Flavone, apigenin and luteolin inhibited cell motility
2.4.3 Flavone, apigenin, and luteolin activate FOXO3a, which is associated with a change in the signal transduction pathway
2.5 Table, Figures and Figure legends ………………………. 25-58
Table 1
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
2.6 Discussion ………………………………………………… 59-65


Chapter 3:
Title of article: Cold-water extracts of Grifola frondosa and its purified active fraction and its purified active fraction inhibit hepatocellular carcinoma in vitro and in vivo
3.1 Abstract …………………………………………………. 66-67
3.2 Introduction ………………………………………………. 68-72
3.3 Material and Methods…………………………………..... 73-81
3.3.1 Bioactive extract from Grifola frondosa
3.3.2 Phenol-sulfuric acid method to determine polysaccharide content
3.3.3 Size fractionation by gel filtration
3.3.4 Molecular size analysis
3.3.5 Cell line and cell culture
3.3.6 MTS assay
3.3.7 Colony formation assay
3.3.8 Wound healing assay
3.3.9 Cell cycle analysis
3.3.10 DsRed-LC3 analysis
3.3.11 Tumor xenograft study
3.3.12 Immunohistochemical staining
3.3.13 Western blot analysis
3.3.14 Statistical analysis
3.4 Results …………………………………………………..... 82-89
3.4.1 GFW inhibits proliferation of human HCC Hep3B cells
3.4.2 GFW induces cell cycle arrest and apoptosis
3.4.3 GFW induces autophagy in Hep3B cells
3.4.4 GFW induced autophagy by inhibiting PI3K and activating JNK
3.4.5 Effects of GFW on the growth of xenograft tumors in nude mice
3.4.6 Isolation of active fractions of GFW by gel filtration chromatography
3.4.6 GFW-GF induced apoptosis and autophagy in Hep3B cells
3.5 Figures and Figure legends…………………………….. 90-128
Table 1
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
3.6 Discussion ………………………….……………………. 129-134
References ……………………………………………………… 135-149
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