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[人類腦下垂體腫瘤轉型基因-1]的過度表達 促進乳癌細胞老化、發炎與轉移的機制

The Role of Human Pituitary Tumor-Transforming Gene-1 (hPTTG1) Overexpression in Oncogene-induced Senescence, Inflammation and Metastasis in Breast Cancer Cells

作者:阮振維
畢業學校:慈濟大學
出版單位:慈濟大學
核准日期:2012-10-02
類型:Electronic Thesis or Dissertation
權限:Copyright information available at source archive--Tzu Chi University....

中文摘要

乳癌是一種複雜性的癌症疾病,在臨床上可以依據細胞的來源、對賀爾蒙的依賴性與癌細胞的分子標記等相關指標,被分類成不同的種類。乳癌的發展是階段性的,從良性增生、惡性轉化到轉移,被認為在每個階段都有不同的基因參與,因此,找到造成乳癌細胞惡性化甚至轉移的關鍵基因,將對乳癌的治療帶來重大突破。
hPTTG1基因最早是在1997 年從大鼠的腦下垂體腫瘤細胞中被找到,並被證實可以造成細胞的癌化。在這15年來,雖然許多文獻證明hPTTG1能在不同種類的腫瘤細胞中,促進癌細胞的惡性轉化、增生與轉移,但也有部分的研究發現,hPTTG1過度表達在特定種類的細胞中,也能導致細胞的老化(senescence)並抑制腫瘤細胞的生長。因此了解hPTTG1基因的過度表達為何造成這些矛盾的差異,是我博士論文的主要研究目標。
我的研究發現,在人類正常乳腺上皮細胞MCF-10A與非轉移性的乳癌細胞MCF-7中,hPTTG1的過度表達會引發細胞的老化反應,並抑制細胞的生長。進一步去了解這個現象的訊息傳導機制,發現hPTTG1的過度表達會促進CXCR2受體的表達,同時也透過活化NF-kappaB轉錄因子訊息,促進CXCR2受體的特異性配體IL-8與GRO悛漯竁F,進而活化CXCR2訊息並引發細胞的老化反應。
我們的深入研究更發現,hPTTG1/CXCR2訊息是透過增加p21蛋白的表達,來抑制細胞週期的進行。在老鼠實驗中,hPTTG1的過度表達明顯抑制了MCF-7腫瘤的生長,若在hPTTG1過度表達的MCF-7細胞中將CXCR2或p21以shRNAs進行抑制,這些細胞的老化反應會受到抑制,並且恢復腫瘤的生長與轉移能力。有趣的是,雖然我們的證據證明了hPTTG1/CXCR2/p21訊息所引發的老化反應可以有效的抑制腫瘤生長與轉移,我們卻也發現老化反應所引發的”老化相關分泌因子(senescence-associated secretory phenotype)”的表現,改變了腫瘤的微環境(microenvironment),使得腫瘤中非老化的癌細胞,有更強的生長與轉移能力。因此,在我們的研究中,我們證明了CXCR2/p21老化訊息的健全與否,決定了hPTTG1過度表達在癌細胞中的角色,若CXCR2/p21訊息健全,hPTTG1的過度表達將引發老化反應並抑制腫瘤細胞的生長,若CXCR2/p21訊息產生缺失,那hPTTG1的過度表達將會強烈的促進腫瘤細胞的生長與轉移。我的博士論文解決了長久以來不同研究對hPTTG1角色所發現的矛盾,也更進一步發現hPTTG1過度表達對腫瘤微環境的影響,希望這樣的研究基礎,能夠使乳癌治療在將來有更顯著的突破。

英文摘要

hPTTG1 (human pituitary tumor-transforming gene 1) is an oncogene overexpressed in breast cancer and several other types of cancer, but the role of hPTTG1 in promoting the proliferation, migration, invasion, metastasis and senescence of cancer cells remains ambiguous. In this study, I investigated the mechanism of hPTTG1-induced senescence as well as its role in breast cancer progression and metastasis. Herein, I showed that hPTTG1 overexpression reinforced senescence in breast cancer cells through the co-upregulation of CXCR2 and its ligands. Furthermore, hPTTG1 overexpression activated NF-kappaB signalling to transactivate the expression of IL-8 and Gro to execute CXCR2 signalling in MCF-7 cells. When CXCR2 expression was knocked down in hPTTG1-overexpressing MCF-7 cells, hPTTG1-induced senescence was abrogated by alleviating CXCR2-induced p21 expression. In a mouse model, CXCR2-mediated senescence limited hPTTG1-induced tumor growth and metastasis. CXCR2 knockdown in hPTTG1-overexpressing MCF-7 tumors dramatically accelerated tumor growth and metastasis. Our in vitro and in vivo results demonstrated that hPTTG1 overexpression reinforces senescence through CXCR2 signalling, and the evasion of CXCR2/p21-dependent senescence was critical to hPTTG1 exerting its oncogenic potential. Interestingly, although CXCR2-dependent senescence restrained hPTTG1-induced tumor progression, when MCF-7 cells and hPTTG1-overexpressing MCF-7 cells were co-transplanted into the mammary fat pad of SCID mice, hPTTG1-overexpressing senescent cells created a metastasis-promoting microenvironment that promoted lung metastasis of the MCF-7 cells. Immunohistochemical analysis of human breast tumor samples also confirmed the importance of the hPTTG1/CXCR2 axis in promoting breast cancer metastasis. Taken together, our findings provide molecular insights into hPTTG1-induced senescence and identify a novel mechanism by which hPTTG1 promotes metastasis by regulating the senescence-associated microenvironment.


口試委員 - 曾若嘉

口試委員 - 王陸海

召集人 - 莊育裡

口試委員 - 林銘德

指導教授 - 陳紀雄


 

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