系統識別號 U0026-0912201011071800
論文名稱(中文) 半乳糖凝集素-1在癌症進程所扮演的角色
論文名稱(英文) The Role of Galectin-1 in Cancer Progression
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 99
學期 1
出版年 99
研究生(中文) 吳明恆
研究生(英文) Ming-Heng Wu
學號 s5893114
學位類別 博士
語文別 英文
論文頁數 104頁
口試委員 指導教授-陳玉玲
中文關鍵字 乳糖凝集素  轉移  口腔鱗狀上皮細胞癌  癌症纖維母細胞  侵犯 
英文關鍵字 Galectin-1  metastasis  OSCC  CAF  invasion 
中文摘要 Galectin-1 是一種β-半乳糖結合凝集素(lectin),過去的文獻報導顯示半乳糖凝集素-1的表現量和早期口腔鱗狀上皮細胞癌症的預後有緊密的相關性,半乳糖凝集素-1在癌症組織中的侵犯前緣及間質組織有高度表現的狀況,轉移到淋巴結的腫瘤細胞也會高度表現半乳糖凝集素-1,這暗示著半乳糖凝集素-1過度表現在腫瘤細胞或間質細胞都會促進口腔鱗狀上皮細胞癌症的進程和轉移。但是它在癌症侵犯及轉移中的作用機制仍然不清楚。在本篇研究中,我們發現在口腔鱗狀上皮癌和肺腺癌的細胞株中半乳糖凝集素-1的表現都和它們的侵犯能力有相關性,降低半乳糖凝集素-1的表現量也的確抑制腫瘤細胞的侵犯能力,研究其作用機制發現半乳糖凝集素-1可促進間質金屬蛋白酶2, 9的表現和活化Cdc 42的方式來促進腫瘤侵犯的能力,Cdc42是一種屬於Rho家族的小GTPase,能夠增加腫瘤細胞骨架filopodia的數目及和長度,我們發現免疫缺乏老鼠以尾巴靜脈注射的方式打入過度表現半乳糖凝集素-1的癌細胞產生較高的轉移現象。這些結果證明半乳糖凝集素-1能直接的加強腫瘤細胞的侵犯和轉移能力。探討半乳糖凝集素-1在腫瘤間質細胞的角色,發現在口腔鱗狀上皮細胞癌間質組織中的半乳糖凝集素-1的表現量和 -平滑肌動蛋白(一種癌症纖維母細胞標誌)的表現量有正相關性。降低半乳糖凝集素-1的表現會減少癌症纖維母細胞的一些特性,例如降低-平滑肌動蛋白的表現量和降低產生細胞外間質蛋白的能力,並且可以有效的抑制癌症纖維母細胞培養液促進癌細胞爬行及侵犯的能力。而作用機制的剖析發現,阻斷半乳糖凝集素-1的表現大幅降低癌症纖維母細胞中單核球趨化蛋白-1的產生,單核球趨化蛋白-1藉由和它的接受器CCR2的結合來促進癌細胞的爬行,在癌症纖維母細胞的培養液加入中和單核球趨化蛋白-1活性的抗體能夠有效抑制癌細胞的爬行。最後,我們在小鼠實驗中發現降低半乳糖凝集素-1的表現能夠有效減少癌症纖維母細胞促進的口腔鱗狀上皮細胞癌腫瘤生長及轉移的能力,總結來說,我們的結果明顯的指出半乳糖凝集素-1在癌細胞和癌症纖維母細胞扮演特定的角色,標靶降低半乳糖凝集素-1表現在癌細胞和癌症纖維母細胞可以抑制口腔鱗狀上皮細胞癌症的進程和轉移。
英文摘要 Galectin-1 (Gal-1) is a β-galactose-binding lectin; its expression level has been reported to correlate with the poor prognosis of early-stage oral squamous cell carcinoma (OSCC). Gal-1 is highly expressed in the invasive front and the stroma of primary tumors. Besides, cancer cells of metastatic lesions in the lymph nodes also show high level of Gal-1 expression. The results suggest that Gal-1 overexpressed in cancer cells and stromal cells may promote OSCC progression and metastasis. However, the mechanisms of Gal-1 mediated tumor progression are not fully clear. In this study, we found increased Gal-1 expression was closely associated with its high invasion ability in lung adenocarcinoma and OSCC cell lines. Modulation Gal-1 expression in cancer cells regulated their invasion ability. Mechanism studies revealed that Gal-1 promoted tumor invasion mainly by up-regulating matrix metalloproteinase (MMP)-9 and MMP-2 and by enhancing the activation of Cdc42, a small GTPase and member of the Rho family, thus increasing the number and length of filopodia on tumor cells. Furthermore, Gal-1-overexpressing cancer cells had higher metastatic abilities in tail vein metastasis assays in vivo. The results demonstrated that Gal-1 directly enhanced tumor invasiveness. To dissect the role of galectin-1 in carcinoma associated stroma, we found Gal-1 overexpression in carcinoma-associated fibroblasts (CAFs) was positively associated with alpha-smooth muscle actin (-SMA, a CAF marker) in the stroma of OSCC specimens. Gal-1 knockdown reduced activated CAF characteristics such as reduced -SMA expression and extracellular matrix production. Blockage of Gal-1 expression significantly inhibited CAF-conditioned medium-induced tumor cell migration and invasion. Mechanistic dissection showed that blocking Gal-1 expression in CAFs dramatically reduced the production of monocyte chemotactic protein-1 (MCP-1/CCL2). MCP-1 induced the migration of OSCC cells by binding to its receptor, CCR2, but adding MCP-1 neutralizing antibody to CAF-conditioned medium abolished migration. Gal-1 knockdown in CAFs significantly reduced CAF-augmented tumor growth and metastasis in vivo. Taken together, our findings showed the distinct role of Gal-1 in cancer cells and CAFs and targeting Gal-1 in CAFs and cancer cells inhibited OSCC progression and metastasis.
論文目次 Contents
Contents………………………………………………………… 1
List of Figures…………………………………………………… 3
Abstract in Chinese…………………………………………… 5
Abstract………………………………………………………………… 7
Acknowledgments………………………………………………… 9
Abbreviation……………………………………………………… 10
Introduction…………………………………………………… 12
1. Tumor metastasis ………………………………………… 12
2. Head and neck squamous cell carcinoma…………… 13
3. Carcinoma associated fibroblasts ……………… 13
4. The biological roles of Galectin-1………………… 15
5. The association of galectin-1 and cancer………… 17
6. Galectin-1 in tumor growth……………………………… 18
7. Galectin-1 in cell adhesion and migration……… 20
8. Galectin-1 in angiogenesis……………………………… 20
9. Galectin-1 in immune-escape…………………………… 21
Rational and Specific Aim……………………………………… 23
Materials and Methods…………………………………………… 24
Results…………………………………………………………………… 33
Part 1: The role of galectin-1 in cancer cells…………… 33
Part 2: The role of galectin-1 in carcinoma-associated fibroblasts…………………………………………………………… 38
Discussion………………………………………………………………… 43
1. The clinical implication of Gal-1 enhanced MMP-2, -9 productions and its mediated small GTPase activation… 43
2. How does Gal-1 modulate MMP-2 and MMP-9 expression and filopodia formation in OSCC cells? ……………………… 45
3. The clinical implication of Gal-1 mediated fibroblast activation and MCP-1 expression……………………47
4. How is galectin-1 overexpressed in cancer cells and CAFs?…………………………………………………………………… 49
5. Developing strategies to target Gal-1……………… 50
Conclusion……………………………………………………………… 52
References……………………………………………………………… 53
Figures…………………………………………………………………… 72
Appendix………………………………………………………………… 97
Curriculum Vitae…………………………………………………… 103

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