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研究生:楊德芳
研究生(外文):Te-Fang Yang
論文名稱:結締組織生長因子於人類前列腺癌侵襲與轉移之角色
論文名稱(外文):The Role of Connective Tissue Growth Factor in Prostate Cancer Invasion and Metastasis
指導教授:周逸鵬張正琪張正琪引用關係
指導教授(外文):Yat-Pang ChauCheng-Chi Chang
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:解剖暨細胞生物學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:61
中文關鍵詞:結締組織生長因子前列腺癌
外文關鍵詞:connective tissue growth factoprostate cancer
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中文摘要
前列腺癌在西方國家的致死率排名第二,該種惡性腫瘤的浸襲及遠端轉移往往是治療失敗的主要原因。結締組織生長因子(CTGF)屬於CCN 家族的一員,是一種分泌型的蛋白,參與了許多生物基本功能,如細胞增生、細胞凋亡、黏附,細胞外基質製造,細胞遷移,和血管新生等。而近年來,在纖維化與癌症的發展等病理的過程中,也發現此家族的蛋白扮演了重要的角色。在前人的研究中指出,結締組織生長因子似乎在參與不同癌症中的角色是相異的,但在前列腺癌的角色,卻仍不甚清楚。因此,我們企圖探討人類結締組織生長因子在前列腺癌中的重要性,以及可能參與此種癌症發展過程之調控機轉。
在本篇研究中,我們發現結締組織生長因子的蛋白質高度表現在前列腺癌病人的腫瘤組織中,也發現該蛋白在三株常用的前列腺癌細胞株中 (LNCaP, DU145和PC3) 都有表現,且與細胞浸襲能力成正相關,顯示結締組織生長因子可能參與並調控前列腺癌之浸襲與轉移過程。此外在短暫轉殖負調控結締組織生長因子的核酸片段以阻斷結締組織生長因子表現後,可以抑制前列腺癌細胞轉移之浸襲能力。同樣的,利用過度表達結締組織生長因子質體轉殖來增加結締組織生長因子表現,與處理結締組織生長因子之重組蛋白後,也提高了前列腺癌細胞株之浸襲能力,顯示結締組織生長因子正向參與在調控前列腺癌細胞轉移的機轉中。相反的我們在惡性度較高的前列腺癌細胞株中暫時或穩定剔除結締組織生長因子的表現,發現可以顯著抑制前列腺癌細胞轉移之浸襲能力,並可抑制癌細胞生長。綜合以上實驗結果,結締組織生長因子可能為促前列腺癌生長及進展之致癌基因,可有潛力發展為前列腺癌之之生物指標,並有機會運用在前列腺惡性腫瘤轉移之臨床治療與檢測上。
Abstract
Prostate cancer is the second leading cause of cancer death in Western countries, and the invasion and distal metastasis are the major causes of treatment failure of prostate cancer. Connective tissue growth factor (CTGF), a secreted matricellular protein of CCN family, engages a wide variety of biological and pathological processes including fibrosis, angiogenesis, proliferation, apoptosis, and cancer progression. Recent studies demonstrated that CTGF seems to have opposite roles in different cancers, and the role in prostate cancer is still unknown. We here investigated the biological roles and its underlying mechanism of CTGF in human prostate cancer. LNCaP, DU145, and PC-3 cells with low, moderate, and high metastatic potential, respectively, were used in this study. We found that endogenous CTGF expression positively correlated with invasive and metastatic potential of prostate cancer cells. Thus, small hairpin RNA (shRNA) constructs for targeting human CTGF were used to knockdown the CTGF expression. The decrease of CTGF protein in PC-3 cells resulted in a dramatic reduction of cell invasion. Moreover, overexpression of CTGF or recombinant CTGF treatment increased the invasion ability of LNCaP cells. These data suggest that CTGF may be an oncoprotein during human prostate cancer progression, and could be a potential clinical target and biomarker for prostate cancer therapy.
Contents

Signature Page ------------------------------------------------------------------ 2
Thesis Approval Form---------------------------------------------------------- 3
Acknowledgments ---------------------------------------------------------------4
Chinese Abstract----------------------------------------------------------------- 5
English Abstract------------------------------------------------------------------ 7
Introduction-----------------------------------------------------------------------8
Materails and Methods----------------------------------------------------------16
Results-----------------------------------------------------------------------------25
�� Endogenous CTGF mRNA and protein expression were associated
with invasion ability in human prostate cancer cells------------------25
�� CTGF induced an invasive phenotype in prostate cancer cells-------26
�� CTGF expression was significantly positively correlated with
clinical outcome of prostate adenocarcinoma-------------------------29
Discussion------------------------------------------------------------------------ 31
References------------------------------------------------------------------------34
Figures and Figure Legends----------------------------------------------------46
Table-------------------------------------------------------------------------------61
Reference
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