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標題: 趨化激素CXCL1促進血管新生腫瘤生長及轉移調控機制之探討
CXCL1 Mediated CXCL12/CXCR4 and COX-2/PGE2 Gene Expression Enhances Angiogenesis, Growth and Metastasis
作者: 許美鈴
關鍵字: 商品化;Gastric cancer;醫學技術, 生物技術;胃癌;趨化激素;轉錄因子;血管新生;腫瘤生長;轉移;臨床治療;transcription factor CEBPβ;CXCL1;angiogenesis;growth;metastasis;therapeutic
胃癌位居全球癌症死亡的第二位。經由臨床病人檢驗檢體分析發現:趨化激素(CXCL1)與胃癌腫瘤癌化進展及轉移有十分密切之關聯性。為了促使有效的治療,探討基因訊息的表現暨釐清調控機轉即更顯重要。在過去一年初步研究成果中發現,CXCL1誘導胃癌細胞媒介物質PGE2及CXCL12導致血管新生腫瘤生長及轉移現象已有令人興奮的結果。我們已經著手研究該主題,並且積極發展或尋求新穎有效、作用在特定分子的抗腫瘤藥物(厚朴酚),進而應用於臨床上促使抗腫瘤療效更好、副作用反應更小將是理想的策略。CXCL1在血管新生、腫瘤生長及轉移現象扮演重要的角色。由過去研究發現它與趨化激素IL-8序列分析有著極高的相似度,暗示著兩者有類似的功能。然而過去有關CXCL1分子作用機轉卻十分有限,特別是影響與胃癌腫瘤相關的功能性基因,訊息傳遞及治療的可行性。本研究係針對CXCL1誘導胃癌細胞血管新生、腫瘤生長及轉移為腫瘤生物學探討模式主軸,進一步之訊息傳遞及轉錄因子的參與機制。有鑒於腫瘤治療的重要性,我們認為這個研究模型值得深入探討。我們初步的研究發現:1-2. CXCL1誘導胃癌細胞媒介物質PGE2及CXCL12大量生成,導致血管新生腫瘤生長及轉移現象。3-4. CXCL1誘使COX-2及CXCR4蛋白表達顯著增加。5. CXCL1增加轉錄因子CEBPβ之活性。6. CXCL1促使致癌基因Tpl-2活性增加,特別是在致癌基因Tpl-2的絲氨酸的磷酸化而非蘇胺酸的磷酸化。【計畫重點】基於現有的初步研究以及既往之報導發現,我們提出更進一步的研究促使CXCL1對分子機制及腫瘤基因的調控有更深入的瞭解。我們擬以四年時間探討下列重點:1-2.致癌基因Tpl-2是否調控轉錄因子CEBPβ之活性,進而促進COX-2/PGE2 之生成與CXCL12/CXCR4之表達關聯性。3.分別以過度表達轉錄因子CEBPβ及沉默基因CEBPβ深入探討轉錄因子CEBPβ之重要性。4.以體腫瘤異種移植老鼠探討CXCL1促進癌細胞轉移運用。5.純化合物厚朴酚抑制血管新生腫瘤生長及轉移現象之分子機制及腫瘤基因的調控有更深入的瞭解。6.以化學致癌劑MNNG誘導癌化過程中探討CXCL1可能扮演腫瘤癌化生成之角色。我們的初步研究開啟未來四年的研究可行性暨更多的視野,經由探討及瞭解CXCL1 作用在人類胃癌細胞可能扮演的角色及調控蛋白之機制,進而應用於臨床胃癌病人的治療將有莫大的助益。同時本研究的作業平台,將可以更有效地將基礎研究的成果,應用到國人重要癌症篩檢開發,並提供分子藥理開發成為新藥物的靶點,建構出高特異性、作用更精確的藥物,為發展生技製藥奠定基礎暨提升我國生醫科技水準。

Gastric cancer is the second most common cause of death from cancer in the world. Clinicalspecimen analysis revealed that increased chemokine CXCL1 expressions correlate with enhancedgastric tumor progression and metastasis. To improve the therapeutic results, the exploration ofexpression gene and elucidation of mechanism of tumor progression are considered to be of greatimportant. Numerously mediators such as prostaglandin E2 (PGE2), CXCL12 promote gastric tumorgrowth by stimulating angiogenesis, cell invasion, and cell growth, and inhibiting apoptosis. We haveinitiated a study to search for cell signaling events involved in human gastric cancer genetic alterations.Molecules that regulate tumor-associated angiogenesis provide promising therapeutic targets fortreatment of gastric cancer as indicated by the recent development of the novel anti-angiogenic agentHonokiol.CXCL1 (melanoma growth-stimulatory activity/growth-regulated protein alpha), plays a majorrole in inflammation, angiogenesis, tumorigenesis, and metastasis. CXCL1 has extensive sequencesimilarity to the IL-8, suggesting functional similarities. In a variety of cancer cell lines, rodent tumormodels and human cancer biopsies, the level of CXCL1 is elevated, correlating with increasedtumorigenicity. Pathological conditions such as tumor growth and malignancy correlate withneutrophil-activating properties of CXCL1. Evidence shows that CXCL1 correlation with cancerprogression and carcinogenesis. However, little is know about the mechanism and targeted therapyunderlying their molecules action in gastric cancer.Our preliminary data showed that: (1) CXCL1 induces cancer cell growth by in vitro cellproliferation assay, soft agar assay and in vivo tumor growth. (2) CXCL1 promotes angiogenesis by invitro tube formation, CAM assay, in vivo matrigel plug assay, ex vivo aorta ring assay. (3) CXCL1 upregulates cancer cell metastasis by in vitro cancer cell migration, invasion assay, MMP activity and invivo animal study peritoneal metastasis. (4) CXCL1-induced mediators, especially chemokines(CXCL12) and prostaglandins (PGE2) production by ELISA assay. CXCL1-evoked CXCR4 or COX-2mRNA and protein expression in gastric cancer cells and HUVECs. (5) Increased expression ofCXCL1 has been attributed to constitutive activation of transcription factor CEBPβ throughmitogen-activated protein kinase, but not AP-1 and SP-1. The novel pathway is different fromprevious study in the NF-κB activation. (6) CXCL1-induced tumor progression locus 2 (Tpl-2)proto-oncogene kinas activity through serine phosphorylation but not threonine phosphorylation.We propose a four years project to focus on: (1) To elucidate the underlying mechanism thatTpl-2 may trigger CEBPβ activity result in angiogenesis via the COX-2 and PGE2 dependent pathwayin gastric carcinoma. (2) To investigate the underlying mechanism that Tpl-2 may trigger CEBPβactivity result in angiogenesis via the CXCL12/CXCR4 dependent pathway in gastric carcinoma (3)Further to determine involves in CXCL1 enhances angiogenesis and tumor growth signaling cascadeand regulates mechanisms through CEBPβ activation in human gastric cancer. (4) Further to verifyCXCL1 exerts biological activity in cell metastasis and enhances peritoneal dissemination inorthotopic xenograft mouse models. (5) Further to verify the promising drug Honokiol exertsbiological activity in suppression of cancer angiogenesis and metastasis in vivo and in vitro were becarried out. (6) Further to determine the role of CXCL1 in stomach carcinogenesis and tumorigenesisprocess were being achieved.Our results should facilitate the understanding of this expanded role in promoting tumor biologyand provide the therapeutic possibility as a potential chemotherapeutic agent in open new doors totherapeutic intervention.
其他識別: NSC99-2320-B005-003-MY3
Appears in Collections:生醫工程研究所

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