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系統識別號 U0026-1810201922282700
論文名稱(中文) 探討細胞內Cathepsin S調控細胞爬行及侵犯能力的分子機轉
論文名稱(英文) Studying the Molecular Mechanisms of Cathepsin S in Regulating Cell Migration and Invasion
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 108
學期 1
出版年 108
研究生(中文) 林筱涵
研究生(英文) Hsiao-Han Lin
電子信箱 sallyluckyday@gmail.com
學號 S58001454
學位類別 博士
語文別 英文
論文頁數 78頁
口試委員 指導教授-張俊彥
口試委員-沈孟儒
口試委員-洪文俊
召集委員-洪澤民
口試委員-陳鴻震
中文關鍵字 組織蛋白酶 S (cathepsin S, CTSS)  溶體半胱胺酸蛋白酶 (lysosomal cysteine protease)  焦點黏連 (focal adhesion)  鈣池調控的鈣離子流入 (store-operated calcium entry, SOCE)  轉移 (metastasis) 
英文關鍵字 cathepsin S (CTSS)  lysosomal cysteine protease  focal adhesion  store-operated Ca2+ entry (SOCE)  metastasis 
學科別分類
中文摘要 組織蛋白酶 S (cathepsin S, CTSS) 被證實是一種能藉由分解細胞外基質 (extracellular matrix, ECM) 促進細胞爬行及侵犯能力的溶體半胱胺酸蛋白酶,但 CTSS 是否會調控轉移的其他細胞內機制仍未知。除此之外,雖然 CTSS 被認為是具潛力的癌症治療標靶,但小分子 CTSS 抑制劑造成的分子層面影響及治療效率仍不清楚。因此在本研究中,我們各別用 siRNA 及具高度專一性的抑制劑 RJW-58 抑制 CTSS 的表現量與酵素活性來探討 CTSS 調控細胞爬行及侵犯能力的新穎細胞內機制。我們利用活體外功能性實驗 (in vitro functional assays)、西方墨點法 (western blot analysis) 以及活體移植模式 (in vivo colonization model) 證明 CTSS 確實與細胞貼附能力有正相關。除此之外,我們發現當 CTSS 表現量下降或是活性被抑制都會明顯減少從鈣池調控的鈣離子流入 (store-operated calcium entry, SOCE) 進到細胞內的鈣離子濃度,但並不會影響位於內質網的鈣離子存量感受分子 STIM1 和細胞膜上的鈣池調控鈣離子通道蛋白 Orai1 的表現量,而會受鈣離子影響的下游分子 NFAT1 及 Rac1 的活化更會隨著 RJW-58 濃度增加而降低。蛋白質複合體免疫沉澱法 (protein complex immunoprecipitation, Co-IP) 的結果更進一步證明 CTSS 活性被抑制時會降低 CTSS 與 STIM1 結合。更重要的是,我們利用共軛焦顯微鏡 (confocal microscope) 及超高解析度成像 (super-resolution imaging) 發現當 CTSS 活性被抑制時會造成活化態 STIM1 聚集在內質網並且削弱活化態 STIM1 與微管相關蛋白 EB1 之間的相互作用。總體而言,本研究第一次證明 CTSS 可以藉由調控 STIM1 移動進而影響鈣離子平衡,最終改變細胞爬行及侵犯能力。
英文摘要 Cathepsin S (CTSS), a lysosomal cysteine protease, has been reported to be associated with extracellular matrix (ECM) degradation, thus promoting cell migration and invasion, but whether CTSS regulates other intracellular mechanisms during metastasis remains unknown. Besides, CTSS has been referred to as the potential cancer therapeutic target, but the molecular impact and the efficiency of the small molecule inhibitors of CTSS are still unclear. Hence, we knocked down the expression of CTSS by siRNA transfection, and inhibited the enzymatic activity of CTSS by the highly-selective CTSS inhibitor RJW-58 to study the novel intracellular mechanisms of CTSS in regulating cell migration and invasion. The results of in vitro functional assays, western blot analysis, and an in vivo colonization model demonstrated that CTSS was positively related to cellular adhesive ability. Moreover, both CTSS knockdown and inhibition significantly decreased Ca2+ influx via store-operated Ca2+ entry (SOCE) without changing STIM1 and Orai1 expression levels, while RJW-58 dose-dependently reduced the activation of the Ca2+-dependent downstream effectors, NFAT1 and Rac1. The results of protein complex immunoprecipitation demonstrated that CTSS could bind to STIM1, which was reversed by CTSS inhibition. In addition, confocal microscopy and super-resolution imaging showed that CTSS inhibition led to STIM1 puncta accumulation in the endoplasmic reticulum and reduced the interaction between active STIM1 and EB1. In conclusion, we have demonstrated for the first time that the lysosomal cysteine protease, CTSS, plays an important role in mediating Ca2+ homeostasis by regulating STIM1 trafficking, which leads to the suppression of cell migration and invasion.
論文目次 中文摘要 ………………………………………..………………………………………. III
Abstract ..…………………………………………………………………………………. V
誌謝 ………………………………………..…………………………………………... VII
Contents ……………………………………………………………………………..…... IX
Figure Contents ………………………………………………………………………... XII
1. Introduction ………………………………………………………………………… 1
1.1 Cathepsins ………………………………………………………………………… 1
1.2 Cathepsin S and cancer ………………………………………………………….. 2
1.3 Ca2+ homeostasis in tumor progression …………………………………………. 5
1.4 Cathepsin and Ca2+ homeostasis ………………………………………………… 6
1.5 Store-operated calcium entry ……………………………………………………. 7
1.6 Cathepsin S inhibitors …………………………………………………………. 8
2. Hypothesis and Specific Aims ………………………………………………………. 10
3. Materials and Methods ……………………………………………………………. 11
3.1 Cell cultures ……………………………………………………………………... 11
3.2 siRNA and plasmid transfection ……………………………………………….. 11
3.3 Synthesis of CTSS inhibitor and kinetic assays ……………………………….. 12
3.4 IC50 determination ……………………………………………………………. 12
3.5 Wound-healing assays …………………………………………………………... 13
3.6 Transwell invasion assays ………………………………………………………. 13
3.7 Western blot analysis …………………………………………………………… 14
3.8 Protein complex immunoprecipitation (Co-IP) ……………………………….. 15
3.9 Measurement of mRNA levels ………………………………………………….. 15
3.10 Measurement of single-cell intracellular Ca2+ levels ……………………….. 16
3.11 Analysis of NFAT1 activation ………………………………………………... 16
3.12 Detection of Rac1 activity and Rac1 activation …………………………….. 17
3.13 Immunofluoresence assays ………………………………………………… 18
3.14 Super-resolution imaging ……………………………………………………. 18
3.15 Cell adhesion assays ………………………………………………………….. 19
3.16 In vivo colonization model …………………………………………………… 20
4. Results ……………………………………………………………………………….. 21
4.1 CTSS plays an important role in cell migration and invasion. ……………… 21
4.2 CTSS is positively associated with cell focal adhesion. ……………………… 21
4.3 CTSS positively regulates calcium influx via SOCE and activates Ca2+-
dependent effectors. …………………………………………………………….. 23
4.4 CTSS inhibition alters STIM1-Orai1 interaction by disturbing STIM1
trafficking. ………………………………………………………………………. 24
4.5 CTSS inhibition disturbs STIM1 trafficking by interrupting the interaction
between active STIM1 and EB1. ………………………………………………. 26
5. Discussion and Conclusion …………………………………………………………. 28
6. Future Works ………………………………………………………………………... 32
7. References …………………………………………………………………………… 35
8. Figures and Tables …………………………………………………………………... 43
9. Publication …………………………………………………………………………... 78
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