Part I
慢性骨髓性白血病是第9對與第22對染色體基因發生轉位，導致Bcr-Abl融合致癌蛋白產生所造成的血液腫瘤。我們的研究主要是探討Bcr-Abl如何調控另一個致癌基因－Skp2表現機制。當imatinib或LY294002作用K562細胞能減少Skp2 mRNA的表現，另外，利用Akt shRNA減少細胞內Akt表現量，也造成Skp2的表現降低。Bcr-Abl經由位於Skp2 promoter上-386/-380 bp的Sp1結合位調控Skp2的轉錄。藉由chromatin immunoprecipitation( ChIP)實驗結果可知imatinib會抑制p300與Skp2 promoter上Sp1結合位結合，而當移除細胞中Sp1蛋白質會造成Skp2 mRNA表現減少的情形。因此，Bcr-Abl藉由PI-3 kinase/Akt/Sp1途徑促使Skp2 mRNA表現增加。Bcr-Abl除了增加Skp2 mRNA的轉錄，同時也藉由對Skp2蛋白質轉譯後修飾的機制，造成Skp2 protein表現增加。Imatinib作用後，K562細胞中Skp2蛋白質半衰期縮短，而在Bcr-Abl減少的K562細胞中也有相同情形。抑制Bcr-Abl活性經由APC/Cdh1 E3 ubiquitin ligase增加Skp2蛋白質ubiquitination並藉proteasome使Skp2分解。我們的研究指出imatinib作用後細胞或減少Bcr-Abl表現的細胞中APC/Cdh1抑制蛋白－Emi1亦減少。我們發現Emi1蛋白質的tyrosine 142的磷酸化能調節其蛋白質的穩定性，因此當將tyrosine 142突變後，明顯減低Emi1蛋白質穩定性。Src kinase 抑制劑SU6656會抑制Bcr-Abl表現的K562細胞中Emi1磷酸化，當轉殖v-Src則能阻止imatinib造成Emi1減少的情形。將tyrosine 142突變為phenylalnine(Y142F)會阻斷重組活化態Src kinase對Emi1的磷酸化，且當將wild-type Emi1表現能抵制imatinib引起K562細胞生長週期停滯於G1期的情形，但Y142F突變的Emi1卻無法有這樣的效果。我們的研究中指出Bcr-Abl經PI-3 kinase/Akt/Sp1途徑增加Skp2 mRNA表現外，還能增加Emi1的磷酸化及蛋白質穩定性進而抑制APC/Cdh1的活性，導致Skp2的蛋白質表現上升，因而最後造成CML細胞的增殖。

Part II
Imatinib 在慢性骨髓性白血病的臨床療效是有目共睹的，但對imatinib具抗藥性病人的治療仍是臨床上面臨的重大挑戰。Withaferin A 為一藥用植物－Withania somnifera 的萃取物，在許癌症治療研究中紛紛指出其對許多癌症居具有顯著抗癌作用。我們想了解withaferin A 對imatinib 有反應及具抗藥性之慢性骨髓性白血病是否具有療效。我們發現低濃度withaferin A 會造成對imatinib 有反應的K562 細胞自噬作用，當withaferin A 與細胞自噬抑制劑－chloroquine 同時作用，chloroquine 會抑制細胞自噬作用加強withfaerin A 對細胞造成的細胞凋亡的結果，因此，細胞自噬能保護K562細胞免於withaferin A 所引起細胞凋亡的反應。我們也同時發現withaferin A容易能引發imatinib 抗藥性細胞－T315I 細胞的細胞凋亡現象，此現象是withaferin A 經由造成Akt 的分解所導致的。當以Akt 抑制劑－LY294002 作用於T315I 細胞中能造成細胞凋亡。除此之外，持續活化的Akt 能抵制withaferin A 對T315I 細胞所造成細胞凋亡及caspase 3 活化的結果。我們發現withaferin A 阻止T315I 細胞中hsp90/cdc37/Akt complex 的形成，導致Akt 泛素化並經proteasome 造成其分解。我們也能在Withaferin A 作用後的CML primary cells 細胞凋亡及Akt 減少的現象。我們的研究指出，imatinib 抗藥性細胞－T315I 細胞依賴Akt 所傳遞之存活訊息，而withaferin A 對其的細胞毒殺性較對imatinib 有反應的K562 細胞更強。因此，withaferin A 未來是有效治療imatinib 抗藥性之慢性骨髓性白血病的第二線用藥。

Part III
Suberoylanilide hydroxamic acid (SAHA)是目前正在進行許多癌症包含慢性骨髓性白血病臨床試驗的抗癌藥物，我們想了解在SAHA 所造成抗癌機制中是否有miRNAs 的參與。我們以慢性骨髓性白血病K562 細胞作為研究材料，在短時間及長時間SAHA 作用後，分析K562 細胞中miRNAs 的表現情形。我們發現在SAHA 短時間及長時間作用下持續減少的miRNAs 分別為: miR-92a, miR-199b-5p, miR-223, miR-627 and miR-675 五個miiRNA，我們鎖定與血球分化有極大相關的miR-92a 及miR-223 的表現進行研究。miR-92a 高度表現在K562 細胞及CML 病人週邊白血球中。當以SAHA 作用降低miR-92a 表現的同時可發現腫瘤抑制基因Fbxw7 表現增加。轉殖pri-miR-92a 能抑制SAHA 造成細胞凋亡及Fbxw7 3’-UTR reporter 活性和Fbxw7 表現增加的情形。在我們研究中發現，miR-92a 過度表現於慢性骨髓性白血病中，而SAHA 能抑制慢性骨髓性白血病中miR-92a 表現造成慢性骨髓性白血病細胞凋亡。

Part I
BCR-ABL fusion oncogene results fromt(9;22)(q34;q11) translocation of chromosome is the most common genetic abnormality found in chronic myeloid leukemia (CML) cells . The encoded protein of this fusion gene exhibits constitutively active tyrosinekinase activity which is required for the pathogenesis of CML. We addressed how BCR-ABL oncoprotein increased Skp2 expression. Treatment of Imatinib or LY294002 reduced Skp2mRNA in BCR-ABL-positive K562 cells. Knockdown of AKT by small hairpin RNAalso reduced Skp2 expression. We found that BCR-ABL up-regulated Skp2 via Sp1 because (1) the Sp1 site located at the −386/−380 promoter region was important for BCR-ABL-induced Skp2 promoter activity, (2) chromatin immunoprecipitation assay demonstrated that Imatinib inhibited the recruitment of p300 to the Sp1 site of Skp2 promoter and (3) knockdown of Sp1 reduced Skp2 expression in K562 cells. These results suggest that BCR-ABL controls Skp2 gene transcription via the PI3K/AKT/Sp1 pathway. In addition to transcriptional regulation of Skp2, Bcr-Abl also modulates Skp2 protein stability in these cells. Treatment of Bcr-Abl kinase inhibitor imatinib led to G1 growth arrest accompanied with reduced Skp2 expression. Interestingly, reduction of Skp2 protein occurred prior to down-regulation of Skp2 mRNA suggesting a post-translational control. The half-life of Skp2 protein was significantly attenuated in imatinib-treated cells. Knockdown of Bcr-Abl similarly caused Skp2 protein instability. The decrease of Skp2 was induced by increased protein degradation through the ubiquitin/ proteasome pathway. Our results demonstrated that imatinib treatment or Bcr-Abl knockdown reduced Emi1, an endogenous inhibitor of the E3 ligase APC/Cdh1 which mediated the degradation of Skp2 protein. We found that Emi1 stability was regulated by phosphorylation and mutation of tyrosine 142 significantly reduced the stability. Lines of evidence suggested Bcr-Abl-induced Emi1 phosphorylation was mediated by Src kinase. (1) Src inhibitor SU6656 inhibited Emi1 tyrosine phosphorylation in Bcr-Abl-positive K562 cells. (2) Transfection of v-Src rescued the reduction of Emi1 by imatinib. (3) Mutation of tyrosine 142 to phenylalanine (Y142F) abolished the phosphorylation of Emi1 by recombinant Src kinase. In addition, ectopic expression of wild type but not Y142F mutant Emi1 could counteract imatinib-caused G1 growth arrest. Collectively, our results suggest that Bcr-Abl fusion oncogene increases Emi1 phosphorylation and stability to prevent Skp2 protein degradation via APC/Cdh1-induced ubiquitination and to enhance proliferation of CML cells.

Part II
Although imatinib therapy of chronic myelogenous leukemia is effective, the resistance to imatinib challenges the treatment of this disease. Therefore, search of novel drugs to overcome imatinib resistance is a critical issue in clinic. Withaferin A (WA), an extract of Withania somniferia, exhibits anti-cancer activity on a number of solid tumors. In this study, we investigate the effect of WA on imatinib-sensitive and -resistant CML cells. WA at low concentrations induced autophagy in imatinib-sensitive K562 cells. Co-treatment of chloroquine suppressed autophagy and switched WA-treated K562 cells to apoptosis. This data indicated that autophagy protected K562 cells from apoptosis induced by WA. However, we found that WA triggered caspase activation and apoptosis in imatinib-resistant T315I-positive cells and this effect was associated with down-regulation of Akt activity. Treatment of the AKT inhibitor LY294002 also caused apoptosis in imatinib-resistant T315I-positive cells. Ectopic expression of constitutively active Akt reversed WA-induced apoptosis and caspase activation in imatinib-resistant T315I-positive cells. Molecular study demonstrates that WA repressed the Akt signaling pathway by decreasing Akt expression. We found that WA abolished formation of the hsp90/cdc37/Akt complex to cause Akt degradation through the ubiquitin- and proteasome-dependent pathway. More importantly, WA also induced AKT down-regulation and apoptosis in primary CML cells. Taken together, our results suggested that imatinib-resistant T315I-positive cells were more addicted to Akt-dependent survival pathway and were more sensitive to WA. Therefore, WA could be useful for the treatment of imatinib-resistant CML.

Part III
Suberoylanilide hydroxamic acid (SAHA) is undergoing clinical trial for the treatment of various cancers including chronic myeloid leukemia (CML). We study the potential miRNAs which involved in the anti-cancer effect of SAHA. Microarray analysis revealed that the expression of 57 and 63 miRNAs was significantly changed in K562 cells treated with SAHA for 8h and 24h respectively. Five miRNAs(miR-92a, miR-199b-5p, miR-223, miR-627 and miR-675) were highly expressed in K562 cells and continuously repressed by SAHA. miR-92a and miR-223 known to play important roles in normal and hematopoisis were further characterized. Up-regulation of miR-92a was found in K562 cells and in primary CML cells. Inhibition of miR-92a with SAHA led to increase of the tumor suppressor Fbxw7. Conversely, ectopic expression of pri-miR-92a reversed SAHA-induced apoptosis of K562 cells, increase of Fbxw7 3’-UTR reporter activity and up-regulation of Fbxw7. Collecively, miR-92a is up-regulated in CML cells, and SAHA downregulated the expression of miR-92a to result in apoptosis of CML cells.

Part I: Regulation of Skp2 by Bcr-Abl oncogene in chronic meyloid leukemia cells……………………………………..1-57
英文摘要………………………………………………………………2
中文摘要………………………………………………………………3
研究背景…………………………………………………………...4-13
附圖表…………………………………………………………..7-13
研究目的……………………………………………………………..14
研究材料方法………………………………………………….. ..15-26
研究結果………………………………………………………….27-49
討論……………………………………………………………….50-52
結論……………………………………………………………….53-54
參考資料………………………………………………………….55-57
Part II: Withaferin A induces apoptosis in imatinib-resistant CML cells by repressing the Akt signaling pathway
……………………….…………………………………….58-95
英文摘要…………………………………………………………… 59
中文摘要…………………………………………………………….60
研究背景………………………………………………………….61-66
附圖表………………………………………………………….64-66
研究目的…………………………………………………………….67
研究材料方法………………………………………………….. .68-72
研究結果…………………………………………………………73-88
討論……………………………………………………………….89-90
結論…………………………………………………………………..91
參考資料………………………………………………………….92-95
Part III: Suberoylanilide hydroxamic acid inhibits miR-92a and restores the tumor suppressor Fbxw7 expression in chronic myeloid leukemia cells
……………………….………………………………… 96-128
英文摘要…………………………………………………………….97
中文摘要……………………………………………………………..98
研究背景………………………………………………………...99-105
附圖表……………………………………………………….102-105
研究目的……………………………………………………………106
研究材料方法………………………………………………….107-110
研究結果……………………………………………………….111-122
討論…………………………………………………………………123
結論…………………………………………………………………124
參考資料……………………………………………………….125-128

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