第二十三型絲胺酸蛋白酶的高量表現受第一型雌激素受體於乳癌細胞中之調控對於促進細胞增生之研究

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研究生：	詹濠先 Chan, Hau-Shien
論文名稱：	第二十三型絲胺酸蛋白酶的高量表現受第一型雌激素受體於乳癌細胞中之調控對於促進細胞增生之研究 Investigation of Serine Protease PRSS23 Upregulation by Estrogen Receptor α in Breast Cancer Cell Proliferation
指導教授：	莊永仁
口試委員:	孫玉珠詹鴻霖莊永仁張文祥郭靜娟
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物資訊與結構生物研究所 Institute of Bioinformatics and Structural Biology
論文出版年：	2012
畢業學年度：	100
語文別：	英文
論文頁數：	118
中文關鍵詞：	第二十三型絲安酸蛋白酶、雌激素受體、乳癌、細胞增生
外文關鍵詞：	PRSS23, estrogen receptor, breast cancer, proliferation
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雌激素訊息傳導是已知會影響到乳癌細胞增生、凋亡以及存活的重要機制之一，此訊息傳導會調控下游眾多作用蛋白的產生。自人類基因體計畫執行後，第23型絲胺酸蛋白酶(PRSS23)是一新被發現與鑑定的蛋白質。有趣的是，PRSS23會與雌激素第一型受器(ERα)在乳癌細胞中會一同表現，ERα在臨床上已知是一個對於乳癌腫瘤治療重要的生物標記與投藥治療目標。同時，近期的研究報導亦暗示PRSS23的表現會促進各種不同的癌症的產生。
在此研究中，首先的研究目的是以生物資訊學的方式分析PRSS23的特性。透過分析乳癌的微陣列資料顯示PRSS23與ERα的表現之間有顯著的相關性，因此可以認為PRSS23是一個ERα相關的蛋白質。利用胺基酸序列來進行分析，結果認為PRSS23是一個鹼性、親水性的蛋白質，但在其N端的序列具有一段疏水性質的特異片段。根據立體結構模擬的結果–PRSS23與甘露糖結合蛋白結合絲胺酸蛋白酶第2型在結構上是相似的，推測PRSS23的活化位由三個胺基酸所組成，包括His135，Asp246以及Ser316。這些初步的研究資訊也作為後續的研究提供適當線索。
由於細胞內位置可暗示蛋白質的功能。因此，在進行基因選殖與生產抗PRSS23的抗體之後，此研究的第二個目的是去探討PRSS23於乳癌細胞MCF-7中可能的位置。首先，免疫細胞染色的結果顯示內源性的PRSS23位於細胞核中。另外一方面，透過將eGFP- PRSS23融合蛋白突變的研究，瞭解到PRSS23具有一段特異性的細胞核定位序列(NLS)。這些結果皆顯示PRSS23位於MCF-7細胞的細胞核中。因此，可以合理的去假設PRSS23可能會參與細胞增生、分化、甚至是調控基因的表現。
為了研究PRSS23在乳癌細胞的樣本上是否有顯著地受到ERα調控，此篇研究的第三個目標是去釐清此假設是否成立。PRSS23蛋白質的表現在56位乳癌病人中的檢體皆顯示與ERα的表現有高度的相關性。另一方面，表現ERα的乳癌細胞株中亦表現PRSS23的蛋白質。在試管內的實驗中，亦顯示PRSS23的基因可被雌二醇活化的ERα所調控。另外一方面，PRSS23的RNA被抑制後可以降低MCF-7細胞增生的程度。
這些發現暗示PRSS23對於的雌激素所調控ERα陽性乳癌細胞增生的過程是個重要因子。總結來說，此篇研究的結果顯示PRSS23在乳癌的研究領域中具有潛力成為重要的乳癌治療目標。

Estrogen signaling is one of the known mechanisms to affect breast cancer cell proliferation, apoptosis, and survival, which promotes tumorigenesis by regulating the production of numerous downstream effector proteins. Serine protease PRSS23 is a newly identified protein since the human genome project. Interestingly, in breast cancers, PRSS32 was coexpressed with estrogen receptor α (ERα), which was one of the prominent biomarkers and therapeutic target for breast cancer therapy. Meanwhile, recent studies implied that PRSS23 might be been associated with tumor progression in various types of cancers.
In the present study, the first specific aim was to characterize properties of PRSS23 in silico. Analysis of published breast cancer microarray datasets revealed that the gene expression correlation between ERα and PRSS23 was highly significant among all ERα-associated proteases in breast cancer. Based on the deduced amino acid sequence, the analytical results implied that PRSS23 might be a basic and hydrophilic serine protease with a leading hydrophobic motif. As a result of the model of three-dimensional structural simulation which showed PRSS23 was structurally analogous to mannose-binding protein-associated serine protease 2, His135, and Asp246, and Ser316 might comprise the component residues of the hypothetical catalytic triad of PRSS23. The preliminary information would pave the way for studies in the future.
Subcellular localization may imply the function of a protein. Thus, after gene cloning and anti-PRSS23 production, the second specific aim of this study was to identify the subcellular localization of PRSS23 in MCF-7 breast cancer cells. Firstly, the results of the immunocytochemical study showed endogenous PRSS23 was located at cell nucleus. Furthermore, the nuclear localization sequence of PRSS23 was identified in the study of eGFP-PRSS23 mutagenesis. Therefore, the results indicated PRSS23 was located in the cell nucleus in MCF-7 cells. Accordingly, it was conceivable to hypothesize that PRSS23 might participate in cell proliferation, differentiation, and even gene expression.
To investigate whether PRSS23 expression was regulated by ERα in breast cancer cells, the third specific aim was to clarify the correlation between and functional implication of ERα and PRSS23 in breast cancer. PRSS23 expression was then assessed in 56 primary breast cancers biopsies and eight cancer cell lines. The results consistently confirmed the coexpression of PRSS23 and ERα with clinicopathological significance. In vitro assays in MCF-7 cells demonstrated that PRSS23 expression was induced by 17β-estradiol-activated ERα through an interaction with an upstream promoter region. On the other hand, PRSS23 knockdown may suppress estrogen-driven cell proliferation of MCF-7 cells.
These findings implied that PRSS23 might be a critical component of estrogen-mediated cell proliferation of ERα-positive breast cancer cells. In conclusion, the present study highlights the potential for PRSS23 to be a novel therapeutic target in breast cancer research.

ABSTRACT...............II
摘要...................IV
誌謝...................V
ABBREVIATIONS...............4
CHEMICALS AND REAGENTS...............4
SPECIALIZED TERMS...............4
CHAPTER I - GENERAL INTRODUCTION...............6
1.1- SERINE PROTEASES...............7
1.2- SERINE PROTEASES IN DISEASES...............7
1.3- SERINE PROTEASE PRSS23...............9
CHAPTER 2 - MATERIALS AND METHODS...............11
2.1- ETHICS STATEMENT...............12
2.2- STATISTICS AND DATA ANALYSIS...............12
2.3- CLONING AND CONSTRUCTION OF EXPRESSION PLASMIDS...............12
2.4- CELL CULTURE, CELL TRANSFECTION...............13
2.5- ANTI-PRSS23 ANTIBODY PRODUCTION...............14
2.6- MEMBRANE IMMUNOBLOT...............14
2.7- FLUORESCENT IMMUNOCYTOCHEMISTRY...............15
2.8- SUBCELLULAR FRACTIONATION...............16
2.9- CLONING, SITE-DIRECTED MUTAGENESIS, AND CONSTRUCTION OF EXPRESSION PLASMIDS...............17
2.10- IMMUNOHISTOCHEMISTRY...............18
2.11- QUANTITATIVE REAL-TIME PCR AND SEMI-QUANTITATIVE PCR...............18
2.12- PROMOTER LUCIFERASE REPORTER ASSAY...............19
2.13- CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAY...............19
2.14- FLOW CYTOMETRY...............20
2.15- DOUBLE THYMIDINE CELL GROWTH SYNCHRONIZATION...............20
2.16- SOFT-AGAR COLONY FORMATION ASSAY...............20
CHAPTER 3 - CHARACTERIZATION OF PRSS23 BY BIOINFORMATIC ANALYSIS, EXPRESSION PROFILING AND SUBCELLULAR LOCALIZATION...............22
3.1- BACKGROUND AND SPECIFIC AIMS...............23
3.2- RESULTS...............25
Identification and cloning of PRSS23 cDNA...............26
In silico topological analyses of PRSS23...............27
Identification of PRSS23 catalytic triad...............28
PRSS23 was highly expressed in MCF-7 cells...............28
Subcellular localization studies suggested protease domain was critical to nuclear localization of PRSS23...............29
Mutation of KRK motif disrupted nuclear localization of eGFP-PRSS23 P in MCF-7 cells...............30
CHAPTER 4 - ERΑ UPREGULATED PRSS23 TO MEDIATE BREAST CELL PROLIFERATION...............32
4.1- BACKGROUND AND SPECIFIC AIMS...............33
4.2- RESULTS...............38
Immunohistochemical assays revealed high PRSS23 expression was observed in ERα-positive breast cancer cells...............38
PRSS23 was highly expressed in ERα-positive breast cancer cell lines...............40
Estrogen stimulated PRSS23 expressed in ERα-positive MCF-7 breast cancer cells...............40
Overexpression of stable ERα enhanced PRSS23 expression in MCF-7 cells...............41
E2 driven-ERα upregulated PRSS23 level through upstream promoter region...............43
PRSS23 presented at G2/M transition in MCF-7 cells...............45
PRSS23 RNAi decreased MCF-7 cell proliferation...............46
CHAPTER 5 - DISCUSSION AND PROSPECTS...............48
5.1- SIGNIFICANCE OF THIS STUDY...............49
5.2- PRSS23 AS A REGULATOR...............49
5.3- UNIQUE PROPERTIES OF PRSS23...............51
5.4- ESTROGEN SIGNALING AND PRSS23 IN CANCER...............53
5.4- PRSS23 AND CHROMOSOME REMODELING...............55
BIBLIOGRAPHIES...............57
TABLES...............66
Table 1. The primer list for the cloning of human PRSS23 cDNA...............66
Table 2. The primer list for cloning of promoter region upstream of PRSS23 gene...............67
Table 3. The primer list of qRT-PCR for expression level evaluation in human cell lines    68
FIGURES...............70
Figure 1. Open reading frame of human PRSS23...............70
Figure 2. Domain organization map of PRSS23...............72
Figure 3. Phylogenetic tree of PRSS23’s orthologs...............73
Figure 4. PRSS23 gene expression profile in human tissues...............74
Figure 5. PRSS23 gene expression profile in human cancer tissues...............75
Figure 6. Gene expression analysis of breast cancer patients...............78
Figure 7. Hydrophobicity of PRSS23...............79
Figure 8. Identification of the catalytic triad of human PRSS23...............81
Figure 9. Production of anti-PRSS23 antibody from GST-PRSS23 fusion protein...............82
Figure 10. Overexpression of ectopic PRSS23 was detected by anti-PRSS23 antibody in MCF-7 cells................84
Figure 11. Comparison of anti-PRSS23 by Immunoblot...............85
Figure 12. Endogenous PRSS23 in nucleus of MCF-7 cells...............86
Figure 13. Expression of eGFP-PRSS23 fusion proteins in MCF-7 cells...............88
Figure 14. Mutation of nuclear localization sequence in MCF-7 cells...............89
Figure 15. The estrogens in human    91
Figure 16. The domain organization map of human estrogen receptor α...............92
Figure 17. Estrogen signaling transduction pathway...............93
Figure 18. Both PRSS23 and BRCA genes were stimulated by 17β-estradiol in MCF-7/BUS cell line...............94
Figure 19. Coincidence of ERα and PRSS23 expression in human breast carcinoma...............95
Figure 20. Immunohistochemical classification of anti-PRSS23 staining...............96
Figure 21. Expression of PRSS23 and ERα were analyzed in various human cell lines...............98
Figure 22. E2-activated ERα promoted PRSS23 mRNA level in MCF-7 cells...............100
Figure 23. E2 was irrelevant in upregulation of PRSS23 and pS2 in ERα-negative MDA-MB-231...............101
Figure 24. Increased ERα expression promoted PRSS23 upregulation in MCF-7 cells...............102
Figure 25. ERα stimulated PRSS23 upregulation through the upstream promoter region -2029 to -342 bp of PRSS23 gene in MCF-7 cells...............104
Figure 26. Dynamic expression of PRSS23 in MCF-7 cells...............106
Figure 27. PRSS23 RNAi knockdown attenuated estrogen-driven MCF-7 cell proliferation...............108
Figure 28. PRSS23 was upregulated to enhance proliferation of breast cancer cells...............110
APPENDIX FIGURES...............111
Figure A-1. The Structure of Chymotrypsin and General Mechanism of Serine Protease on Peptide Bond Hydrolysis...............111
Figure A-2. The Simulated Three-Dimensional Structure of PRSS23...............113
Figure A-3. Enzyme Activity Curves of GST-PRSS23-P and tPA Substrate...............115
Figure A-4. The Michaelis-Menten plot of GST-PRSS23-P with different concentration of Boc-VGR-βNA...............116
Figure A-5. The Subcellular Localizations of PRSS23 are Domain-Dependent in Transiently Transfected 293T cells...............117
Figure A-6. Mutation of K257RK259 reduces nuclear transportation...............118


                                

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