RECK是一個內生性抗癌症轉移基因。表現在細胞膜的RECK可以抑制基質金屬蛋白酶 MMP-2、MMP-9及 MT1-MMP的蛋白活性並降低癌症細胞轉移。在臨床癌症組織中裡普遍發現RECK蛋白會呈現較低表現。目前研究了解，細胞膜上醣蛋白RECK與癌症細胞的血管新生和細胞轉移息息相關。但有趣的是從我們的研究發現，RECK除了抑制基質金屬蛋白酶活性外，還能調控訊息路徑。在本篇的第一部分研究中，我們證明RECK能藉由抑制Her2/Neu 形成雙體 (dimerization)所產生的自體磷酸化 (autophosphorylation)，降低下游 ERK與 AKT kinase活性並影響Her2/Neu訊息調控的下游基因表現。在58.8%乳癌組織中偵測 RECK表現下降並且在統計上發現與淋巴節侵犯具有相關，支持 RECK對抗癌症轉移的角色。在第二部分中，將RECK蛋白重新表現在乳癌細胞中會增加ATM和ATR下游訊息和γ-H2AX的磷酸化現象並使受Her2/Neu 路徑調控的DNA修復相關蛋白Jab1及Rad51表現下降，因而阻礙DNA修復，進而增加癌症細胞對藥物的敏感度。第三部分，我們篩選出具有癌症幹細胞指標CD133的胃癌細胞，重新表現RECK蛋白觀察，RECK具有降低癌症幹細胞中stemness相關基因的表現及抑制癌症幹細胞表徵。進一步探討訊息路徑證實，RECK藉由抑制細胞解整合素與金屬蛋白酶家族之蛋白質(ADAM) 活性，使被切割所產生的胞質內片段(NICD 1)減少，進而抑制Notch 1所調控的癌症幹細胞特性。綜合以上，我們發現RECK可藉由調控Her2/Neu及Notch 致癌機制，抑制癌症細胞對藥物抗藥性與癌症幹細胞特性。

Reversion-inducing cysteine rich protein with Kazal motifs (RECK) is an endogenous metastatic suppressor gene, which can inhibit matrix metalloproteinase MMP-2, MMP-9 and MT1-MMP to reduce cancer metastasis. Clinical study showed that RECK is highly express in normal cells, but low in cancers. In general, RECK is a membrane-anchored tumor suppressor glycoprotein and correlate with the angiogenesis and metastasis in vitro and in vivo. Interesting, we found that RECK not only inhibits activity of matrix metalloproteinase, but also regulates some signaling pathways. In the first part of this study, we demonstrated that RECK inhibited Her2/Neu receptor dimerization and autophosphorylation which caused reduction of ERK and AKT kinase activity and down-regulation of Her2/Neu target genes. RECK expression is reduced in 58.8% of breast cancer tissues and is associated with lymph node invasion supporting its anti-metastatic role. In the second part, the data demonstrated that the phosphorylation of ATM and ATR pathways and γ-H2AX foci were detected in restoring the expression of RECK in breast cancer cells. RECK inhibited the Her2 signaling and attenuated the expression of the downstream molecules Jun activation domain-binding protein 1 (Jab1) and the DNA repair protein Rad51 to impede DNA repair and to increase drug sensitivity. In the third part, we selected the CD133-positive cancer stem-like cells from gastric cancer cells. Ectopic expression of RECK induced down-regulation of the expression stemness genes including Nanog, Oct4, Sox2 and the formation of cancer stem cell. In further study, RECK represses stemness gene expression and stem-like properties by inhibiting ADAM-mediated Notch1 shedding and activation. Taken together, we provide evidences that RECK regulates Her2/Neu and Notch oncogenic pathways to repress cancer cell drug resistant and tumorigenic of cancer stem cell.

論文審定書 + ⅰ
Chinese Abstract+ⅱ
English Abstract+ⅲ
Chapter Ⅰ+1
Introduction+2
Materials and methods+6
Results+12
Discussion+16
Figures+20
Appendix Figures+32
Chapter Ⅱ+35
Introduction+36
Materials and methods+40
Results+45
Discussion+49
Figures+53
Chapter Ⅲ+64
Introduction+65
Materials and methods+70
Results+78
Discussion+87
Figures+94
Appendix Figures+114
References+115

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