臺灣博碩士論文加值系統

中文摘要
免疫組織相容性複合體第一型分子它可以呈現由腫瘤抗原衍生的小片段胜肽給CD8+毒殺性T細胞辨識，在誘導宿主對腫瘤的專一性免疫反應中扮演著重要的角色。因此很多類型的腫瘤細胞包括乳癌細胞都利用降低腫瘤細胞內免疫組織相容性複合體第一型分子的表現或使之不表現來當作一種免疫逃避的機制。在本研究當中，我們檢測了一株人類乳癌細胞株MDA-MB-157，此株細胞是由一轉移性乳癌病人身上所分離。經由流式細胞儀實驗，在MDA-MB-157細胞表面不能偵測到免疫組織相容性複合體第一型分子，但是在另一株當做對照組的乳癌細胞株MDA-MB-231細胞表面可以偵測到大量的免疫組織相容性複合體第一型分子。經由西方墨點法分析各種抗原修飾系統的分子以及免疫組織相容性複合體第一型分子的次單位，MDA-MB-157細胞的主要缺陷是缺失了一種12000道耳吞的分子��2–microglobulin (��2m)，��2m對於免疫組織相容性複合體第一型分子的組裝和運輸不可或缺。經由定量的反轉錄聚合酶連鎖反應以及核酸定序，顯示出MDA-MB-157細胞有較少的��2m訊息核醣核酸，而且在編碼區沒有突變，由此結果推測可能是一種後轉錄或後轉譯的��2m缺陷。MDA-MB-157細胞處理蛋白酶體抑制劑MG-132後，��2m蛋白質表現沒有恢復，排除了��2m蛋白質缺失是由於快速的蛋白質分解所造成的原因。為了研究是否有突變存在在��2m 訊息核醣核酸的未轉譯區，利用3’端快速增殖cDNA端點的方法去找出MDA-MB-157細胞的��2m 3’ cDNA端點，但是和對照組的結果相比，偵測不到MDA-MB-157細胞的��2m未轉譯區。除此之外，基因體聚合酶連鎖反應只偵測到��2m基因第一個和第四個外顯子，中間的基因片段都偵測不到。穩定的轉染一個可以編碼出��2m蛋白質的質體進入MDA-MB-157細胞，並且恢復��2m蛋白質表現，指出��2m對於免疫組織相容性複合體第一型分子組裝的重要性。自然殺手細胞毒殺性試驗證實MDA-MB-157細胞可以抵抗自然殺手細胞的毒殺，此結果指出缺乏免疫組織相容性複合體第一型分子的腫瘤細胞會發展出對自然殺手細胞的抵抗性。我們的結果顯示了一種新的基因以及後轉錄的機制，造成乳癌細胞缺乏免疫組織相容性複合體第一型分子以及對自然殺手細胞有抵抗性。這些發現暗示了新的治療策略，在病人身上增加腫瘤細胞對於免疫系統攻擊的感受性。

Abstract
Major histocompatibility complex (MHC) class I molecules play an important role in eliciting host tumor-specific immune response since they present tumor antigen-derived peptides to CD8+ cytotoxic T lymphocytes. Accordingly, loss or downregulaton of MHC class I expression in tumor cells represents an immune escape mechanism utilized by a variety of tumor cell types including breast carcinoma. In this study, we have examined the mechanisms underlying MHC class I loss by the human breast carcinoma cell line MDA-MB-157, which was derived from a metastatic medulallary breast carcinoma lesion. Flow cytometry did not detect MHC class I expression on MDA-MB-157 cells but showed robust expression on MDA-MB-231 cells, a positive-control cell line. Western blot analysis of various antigen processing machinery components and MHC class I subunits in the presence and absence of IFN-�� stimulation identified loss of�n��2–microglobulin (��2m), a 12 kDa subunit critical for MHC class I assembly and transport, as a major defect in MDA-MB-157 cells. Subsequently, quantitative real-time RT-PCR and nucleotide sequencing analysis of the ��2m mRNA in MDA-MB-157 cells detected fair amounts of steady-state ��2m transcripts with no mutations in the coding region, suggesting a post-transcriptional/translational defect. Treatment of MDA-MB-157 cells with the proteasome inhibitor MG-132 did not restore ��2m expression, ruling out accelerated ��2m protein degradation as a possible mechanism. To investigate whether mutations exist in the ��2m mRNA untranslated regions (UTR), Rapid Amplification of cDNA Ends (RACE) was employed but, surprisingly, did not detect any UT fragments compared to controls. Moreover, genomic PCR with walking primers failed to amplify a large internal region of the ��2m gene in MDA-MB-157 cells except exon 1 and exon 4. The critical role of ��2m in the proper assembly and surface expression of MHC class I was indicated by the restoration of HLA class I on MDA-MB-157 cells stably transfected with a ��2m-encoding plasmid. Lastly, cytotoxicity assay demonstrated that MDA-MB-157 cells were resistant to NK cell-mediated cytolysis, suggesting the development of tumor NK-resistance in the absence of HLA class I expression. Taken together, our results revealed novel genetic and post-transcriptional mechanisms underlying total HLA class I loss by a breast carcinoma cell line and its NK-resistance phenotype. These findings may suggest new therapeutic strategies to increase the susceptibility of tumor cells to immune destruction in patients.

CONTENTS
謝誌 I
ABSTRACT II
中文摘要 IV
ABBREVIATIONS VI
CONTENTS VIII
CHAPTER 1 BACKGROUND AND SIGNIFICANCE 1
1.1 GENERAL BACKGROUND 1
1.2 HLA BIOLOGY 3
1.3 ��2-MICROGLOBULIN�n(��2M) 4
1.4 LOSS OF HETEROZYGOSITY (LOH) 6
1.5 HLA PHENOTYPE OF BREAST CARCINOMA CELL LINES 7
1.6 HYPOTHESIS AND SPECIFIC AIMS 8
CHAPTER 2 MATERIALS AND METHODS 9
2.1 CELL CULTURE 9
2.2 ANTIBODIES 9
2.3 CYTOKINES AND PHARMACOLOGICAL INHIBITORS 10
2.4 TOTAL CELL LYSATE PREPARATION 11
2.5 QUANTIFICATION OF PROTEIN CONCENTRATION 11
2.6 WESTERN BLOTTING 12
2.7 FLOW CYTOMETRY 13
2.8 REVERSE TRANSCRIPTION (RT)-PCR 13
2.9 REAL TIME-PCR 14
2.10 RAPID AMPLIFICATION OF CDNA ENDS (RACE) 14
2.12 ELECTROPORATION-MEDIATED GENE TRANSFER 15
2.13 GENERATION OF STABLE TRANSFECTANTS 15
2.14 IN VITRO ISOLATION OF LYMPHOCYTES FROM HUMAN WHOLE BLOOD 15
2.15 NK CELL CYTOTOXICITY ASSAY 16
CHAPTER 3 RESULTS 19
3.1 MDA-MB-157 BREAST CARCINOMA CELLS DO NOT EXPRESS MHC CLASS I MOLECULES ON THE CELL SURFACE. 19
3.2 LACK OF ��2M EXPRESSION IN SPITE OF APM COMPONENT EXPRESSION BY MDA-MB-157 BREAST CARCINOMA CELLS. 19
3.3 EXPRESSION OF ��2M MRNA AND ITS UP-REGULATION BY IFN-�� IN MDA-MB-157 CELLS 20
3.4 THE CODING SEQUENCE OF ��2M MRNA IN MDA-MB-157 CELLS AND THAT IN MDA-MB-231 CELLS ARE 100% IDENTICAL. NO MUTATION EXISTS. 21
3.5 LOH AT THE ��2M GENE IN CHROMOSOME 15 IN MDA-MB-157 CELLS. 22
3.6 ��2M PROTEIN EXPRESSION WAS NOT RESTORED IN MDA-MB-157 CELLS AFTER TREATMENT WITH PROTEASOME INHIBITOR MG-132 AND/OR DNA DEMETHYLATING AGENT 5-AZA-2’-DEOXYCYTIDINE (5ADC). 22
3.7 3’ UTR OF MDA-MB-157 Β2M MRNA COULD NOT BE AMPLIFIED BY 3’RACE. 23
3.8 GENOMIC PCR WITH WALKING PRIMERS FAILED TO AMPLIFY A LARGE INTERNAL REGION OF THE ��2M GENE IN MDA-MB-157 CELLS EXCEPT EXON 1 AND EXON 4. 24
3.9 MHC CLASS I EXPRESSION WAS RESTORED ON MDA-MB-157 CELLS AFTER STABLE TRANSFECTION WITH ��2M -ENCODING PLASMIDS. 24
3.10 MDA-MB-157 CELLS COULD NOT BE LYSED BY NK CELLS ISOLATED FROM HUMAN PERIPHERAL BLOOD AND DID NOT EXPRESS NKG2D LIGAND MICA ON THE CELL SURFACE. 25
CHAPTER 4 CONCLUSIONS AND DISCUSSION 27
CONCLUSIONS 27
DISCUSSION 27
CHAPTER 5 FUTURE DIRECTIONS 30
REFERENCES 31
TABLES 37
TABLE 1. MOLECULAR DEFECTS UNDERLYING CLASSICAL HLA CLASS I ANTIGEN ABNORMALITIES CAUSED BY ��2M MUTATIONS IN MALIGNANT CELLS 37
TABLE 2. RT-PCR PRIMER LIST 38
TABLE 3. REAL TIME-PCR PRIMER LIST 39
TABLE 4. RACE-PCR PRIMER LIST 40
TABLE 5. ��2M GENOMIC PCR PRIMER LIST 41
FIGURES 42
FIGURE 1. MHC CLASS I MOLECULES ARE CRUCIAL FOR CD8+ T CELL RECOGNITION AND DESTRUCTION OF TUMOR CELLS. 42
FIGURE 2. IMMUNE SELECTION OF HOT-SPOT ��2M GENE MUTATIONS. 44
FIGURE 3. ANTIGEN PROCESSING MACHINERY 45
FIGURE 4. ANALYSIS OF A PANEL OF BREAST CARCINOMA CELL LINES FOR HLA CLASS I, HLA-A, AND HLA-B,-C EXPRESSION BY FLOW CYTOMETRY. 46
FIGURE 5. MDA-MB-157 BREAST CARCINOMA CELLS DO NOT EXPRESS MHC CLASS I MOLECULES ON THE CELL SURFACE. 47
FIGURE 6. LACK OF ��2M EXPRESSION IN SPITE OF APM COMPONENT EXPRESSION BY MDA-MB-157 BREAST CARCINOMA CELLS. 48
FIGURE 7. EXPRESSION OF ��2M MRNA AND ITS UP-REGULATION BY IFN-�� IN MDA-MB-157 CELLS. 50
FIGURE 8. THE CODING SEQUENCE OF ��2M MRNA IN MDA-MB-157 CELLS AND THAT IN MDA-MB-231 CELLS ARE 100% IDENTICAL. NO MUTATION EXISTS. 51
FIGURE 9. LOH AT THE ��2M GENE IN CHROMOSOME 15 IN MDA-MB-157 CELLS. 53
FIGURE 10. ��2M PROTEIN EXPRESSION WAS NOT RESTORED IN MDA-MB-157 CELLS AFTER TREATMENT WITH PROTEASOME INHIBITOR MG-132 AND/OR DNA DEMETHYLATING AGENT 5-AZA-2’-DEOXYCYTIDINE (5ADC). 54
FIGURE 11. 3’ UTR OF MDA-MB-157 ��2M MRNA COULD NOT BE AMPLIFIED BY 3’RACE 55
FIGURE 12. GENOMIC PCR WITH WALKING PRIMERS FAILED TO AMPLIFY A LARGE INTERNAL REGION OF THE ��2M GENE IN MDA-MB-157 CELLS EXCEPT EXON 1 AND EXON 4. 58
FIGURE 13. MHC CLASS I EXPRESSION WAS RESTORED ON MDA-MB-157 CELLS AFTER STABLE TRANSFECTION WITH ��2M -ENCODING PLASMIDS. 60
FIGURE 14. MDA-MB-157 CELLS COULD NOT BE LYSED BY NK CELLS ISOLATED FROM HUMAN PERIPHERAL BLOOD AND NO MICA EXPRESSION ON THE CELL SURFACE. 63

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