- 學位論文
新穎醣胺多醣結合胜肽於表皮癌細胞移行與侵襲的調控作用
Regulatory effects of novel glycosaminoglycan binding peptides on epithelial cancer migration and invasion
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摘要
惡性腫瘤蟬聯全球十大死因首位，傳統化療藥物無法有效運送至腫瘤組織，易使腫瘤復發與轉移，導致癌症治療成果有限。抗癌胜肽藥物與傳統化療藥物作用機制不同、且具有專一性腫瘤標靶與低毒性反應之優點，因此為具潛力的新穎抗癌用藥。本實驗室率先於人類嗜酸性白血球陽離子蛋白(human eosinophil cationic protein、hECP)中核心硫酸乙醯肝素結合區域(heparan sulfate binding motif)衍生一段新穎性醣胺多醣結合胜肽(GAG-binding cell penetrating peptide、GBPHH)，並發現其具備抑癌作用。本研究另行設計三種不同定點突變序列之GBPHH衍生胜肽(GBPHH(C6S)、GBPHL與GBPLL)，以測試其序列與功能之相關性，並發現GBPHH與其衍生胜肽對於人類表皮癌細胞具有不同的細胞結合與細胞穿透能力。以A549人類肺腺癌細胞為例，細胞穿透能力最高的GBPHH及次高的GBPHH(C6S)可明顯抑制此表皮癌細胞移行及侵襲活性，然而具有高細胞結合力與低細胞穿透功能的GBPHL和具有低細胞結合力與低穿透細胞功能的GBPLL則無抑制效果。進一步探討GBPs抑制癌細胞轉移之分子機制，發現GBPHH可降低細胞轉移相關細胞內訊號傳遞蛋白質的磷酸化活性。本研究首次發現GBPHH結合癌細胞表面硫酸乙醯肝素、穿透癌細胞、調控細胞內訊號傳遞、抑制表皮癌細胞移行與侵襲之關聯性。本研究成果可具體貢獻於新型抗癌胜肽設計，化學修飾抗癌藥物合成，開發以GBPHH為基礎之表皮癌細胞用藥新型配方與傳輸系統。
並列摘要
Cancer is a leading cause of mortality worldwide. Conventional chemotherapeutic agents for cancers do not distinguish between malignant and normal cells, leading to only limited success and high recurrence rates. Peptide-based treatments for cancer therapy have been of great interest and potential due to advantages including different regulation mechanisms, specific target to tumor cells, and low toxicity in normal tissues. A sulfated GAG-binding peptide (GBPHH) derived from core heparan sulfate (HS) binding motif of human eosinophil cationic protein (hECP) has been recently identified to have anti-tumor functions. In this study GBPHH and 3 derivates (GBPHH(C6S), GBPHL and GBPLL) with variation in only 1 out of 10 amino acids in sequence displayed distinct binding and penetrating activities toward epithelial cancer cells. Interestingly, migration and invasion activities of epithelial cancer cells were significantly inhibited by GBPHH with higher binding and the highest penetration activities, so as GBPHH(C6S). However, GBPHL with the highest binding and lower penetration activities and GBPLL with the lowest binding and penetration activities showed much weaker inhibitory effects. As for molecular mechanisms, phosphorylation of migration-associated molecules decreased upon treatment with GBPHH. GBPHH as a novel metastatic suppressor which acts through initial GAG binding and cell penetration, involved in modulation of cellular signals of epithelial cancer cells. Understanding sequence dependence and anti-tumor mechanisms of GBPHH provides alternative strategies to design more efficacious peptides, synthesize chemically modified drugs, and develop novel formulation and delivery system of GBPHH-based drugs for anti-epithelial cancer.
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