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研究生： 陳煜塘
Chen, Yu-Tang
論文名稱： 細胞自噬在具有KIT外顯子11缺失的胃腸道基質瘤所扮演的角色
The role of autophagy in gastrointestinal cancer with KIT exon 11 deletion
指導教授： 許凱熙
Hsu, Kai-Hsi
學位類別： 碩士
Master
系所名稱： 醫學院 - 臨床醫學研究所
Institute of Clinical Medicine
論文出版年： 2016
畢業學年度： 104
語文別： 英文
論文頁數： 56
中文關鍵詞： 胃間質細胞瘤 、細胞自噬 、KIT 、ULK1 、Imatinib
外文關鍵詞： Gastrointestinal stromal tumor, Autophagy, KIT, imatinib
相關次數： 點閱：68  下載：0 
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    • 胃間質細胞瘤是一種好發於消化道的間葉細胞瘤，在胃為55%而小腸以及十二指腸為30%的發生率，胃間質細胞瘤常伴隨KIT以及PDGFα基因的突變，KIT是一種原致癌基因率，當此類基因產生突變會使KIT大量表現並活化下游的基因表現。在KIT的突變當中以外顯子11的突變最為常見，突變的類型尤以557-558缺失為最多，除此之外率，在先前的研究也有指出當病人具有外顯子11當中的557-558缺失時會有較差的預後。目前臨床上以Imatinib作為主要的治療用藥，但是在先前研究有指出GIST細胞株會透過細胞自噬使GIST細胞株存活下來，顯示細胞自噬能幫助GIST細胞對治療無反應，因此了解KIT的突變如何調控細胞自噬對治療此疾病是相當重要的，然而目前尚未有研究指出KIT的突變會調控細胞自噬，本研究因而想要釐清KIT突變是否會調控細胞自噬且其作用機制為何。
    從臨床資料顯示有KIT外顯子11缺失的病人當中會有較差的預後，且KIT外顯子11缺失的病人對於Imatinib治療無反應的比例會提升，但這群病人檢體當中細胞自噬的標誌LC-3B form II會有較高的表現量，在細胞存活率測試可以發現到具有KIT外顯子11缺失的細胞株有較高的細胞存活率，但在加入細胞自噬的抑制劑時細胞存活率會隨著濃度上升而降低，同時在細胞中減弱細胞自噬相關基因也會降低其細胞存活率，此外，在動物實驗我們也發現到具有KIT外顯子11缺失的細胞在細胞自噬抑制劑及Imtatinib共同使用之下的組別相較於單獨使用的組別會有較小的腫瘤；透過比較KIT外顯子11是否有突變的細胞株我們發現細胞自噬只有在KIT 外顯子11缺失時才會大量表現，並且在KIT外顯子11缺失的細胞當中發現ULK1磷酸化位置表現量有所不同，而這些不同的磷酸化表現量可能與KIT外顯子11當中細胞自噬高表現量有關。
    在我們的研究當中發現了細胞自噬可能是造成KIT外顯子11缺失的病人有較差預後的其中一個原因，而KIT外顯子11缺失是透過調節ULK1鄰酸化影響細胞自噬，因此，合併使用抑制細胞自噬和Imatinib作為治療胃間質細胞瘤的病人提供一個新的治療方式。

    Gastrointestinal stromal tumor (GIST) is discovered in the gastrointestinal tract. Approximately 55% of primary GISTs are found present in stomach and 30% in duodenum and small intestine. GIST patients have high frequency of mutation of c-KIT or platelet-derived growth factor receptor alpha (PDGFRα). c-KIT mutation are predominantly found in exon 11. Among c-KIT exon 11 mutations, those contain codons 557-558 deletions occupied the highest proportion. In addition, GIST patients with codon 557-558 deletion exhibit worse prognosis as compared with those harboring other c-KIT mutation. Imatinib is a potent KIT inhibitor to treat GIST patients in clinical; however, previous results have demonstrated that GIST cells escape imatinib-induced apoptosis through autophagy in vitro, suggesting that autophagy plays an important role in promoting GIST cell survival during drug treatment. Previously, we have found increased autophagy level in GISTs with c-KIT exon 11 deletions than in those with wild type KIT. In this study we aimed to explore whether autophagy is regulated by c-KIT exon 11 deletions and determine the role of KIT exon 11 deletions-induced autophagy in GIST tumorigenesis, as well as the underlying molecular mechanism.
    We found worse survival in GIST patient with c-KIT exon 11 deletion as compared with those carrying wild type KIT or other c-KIT mutations. Additionally, the autophagy marker LC3-B form II was up-regulated in specimens and GIST tumor cell lines with c-KIT exon 11 deletions. GIST cell viability was decreased after treatment with autophagy inhibitors or knock-down of autophagy-related genes. In an animal model, co-treatment with imatinib and chloroquine (CQ) significantly suppressed tumor growth as compared with either agent alone, suggesting that autophagy might protect tumor cells from imatinib-induced cell death in GISTs. Mechanically, autophagy was found to be up-regulated by c-KIT exon 11 deletions through increased phosphorylation in Ser555 and decreased phosphorylation in Ser757 of ULK1.
    In conclusions, our results demonstrated that KIT exon 11 deletions in GIST cells promote the autophagy activity to promote cell viability, and thus tumor progression in GISTs. Therefore, inhibition of autophagy may be a promising strategy way to overcome imatinib resistance in GISTs.

    中文摘要 I Abstract III Acknowledgement V Contents VII Abbreviation list X Introduction 1 1. Gastrointestinal stromal tumor 1 1-1 Clinical features and pathogenesis 1 1-2 Management of GISTs 2 1-3 Resistance to Imatinib in GISTs 3 2. KIT 5 2-1 c-kit exon 11 deletion 7 3. Autophagy 7 3-1 Mechanism of autophagy 8 3-2 Autophagy regulate cancer cell metabolism 9 3-3 Autophagy as tumor suppressors 10 3-4 Autophagy as tumor promoter 11 Research motive 12 1. Rationale 12 2. Specific Aims 13 3. Significance 13 Materials and Methods 15 Cell lines 15 Transformation 15 Plasmid isolation 16 Transient transfection 17 Protein extraction 18 Western blotting 18 Immunohistochemical analysis 19 Cyto-Immunofluorescence Staining 20 Animal model 20 Cell viability analysis 21 Cell cycle analysis 21 Patients 21 Statistical analysis 21 Result 23 KIT and PDGFRα mutations type express in gastrointestinal stromal tumor 23 GIST patients with c-kit exon 11 deletion have poor survival rate 23 GIST patients with c-kit exon 11 deletion highly express LC3. 24 Autophagy marker LC3 expression correlates with c-kit exon11 deletion in GIST cells. 25 c-kit exon 11 deletion promotes G62 growth. 25 Down-regulation of autophagy is related to G62Δ cell viability 26 G62Δ cells have a strong tumorigenesis ability in a subcutaneous mose model 26 Autophagy inhibition potentiates antitumor activity of imatinib in G62Δ tumors. 27 Only c-kit exon11 deletion rather than other c-kit mutations upregulates autophagy in GIST cells 27 KIT exon11 deletion regulates autophagy may through SRC pathway 28 Discussion and Conclusion 29 References 32 Figures 40 Table 53 Appendix 55 Appendix I. antibodies 55 Appendix II. List of shRNA TRC number 56

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