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博碩士論文 etd-0622111-101545 詳細資訊
Title page for etd-0622111-101545
論文名稱
Title
BMP4透過活化MAPK/ERK訊息傳遞路徑 加速肝癌腫瘤細胞的增殖與蔓延
BMP4 activates MAPK/ERK signaling pathway to increase tumor cell proliferation and migration of hepatocellular carcinoma
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
64
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2011-06-16
繳交日期
Date of Submission
2011-06-22
關鍵字
Keywords
有絲分裂、細胞週期、惡性腫瘤、肝臟腫瘤發生、G2/M 階段檢查點
malignancy, cell cycle, hepatocarcinogenesis, G2/M phase Checkpoint, Mitosis
統計
Statistics
本論文已被瀏覽 5681 次,被下載 1322
The thesis/dissertation has been browsed 5681 times, has been downloaded 1322 times.
中文摘要
在台灣,肝癌是最常見的內臟惡性腫瘤疾病,具有高罹患率且難以預測的特性。BMP4屬於TGF-β家族蛋白,目前被了解是一種可以活化多種訊息傳遞途徑發揮其生物性影響的多功能細胞素,BMP家族蛋白也被認為能夠促進或抑制癌症的演進。然而,目前BMP4在肝臟癌症發生的調控機制仍未被確定。在我們的研究中,證實BMP4和其受器,BMPR1A,在病人檢體有高度表現的現象以及在活體外實驗證實BMP4可以促進肝癌細胞株的生長及其移動性。我們也發現BMP4可以誘導CDK1和cyclinB1被高度調節以及加速細胞週期的進行。BMP4誘發的細胞型態改變除了可以透過典型的SMAD的訊息傳遞路徑外,也可以透過活化MEK的路徑。然而,由Smad4表現被抑制的肝癌細胞株仍然可以導致CDK1和cyclinB1的高表現,我們認為BMP4誘導細胞增生不是透過典型SMAD的傳遞途徑。進一步,利用傳遞途徑選擇性抑制劑,我們歸納認為BMP4導致CDK1以及cyclinB1的mRNA和其蛋白被誘導表現,是透過MEK/ERK途徑活化所致。在免疫缺失活體老鼠實驗中,當BMPR1A表現被抑制後,腫瘤生長能力相較對照組有顯著地降低的現象。整體來說,我們的發現顯示在肝癌腫瘤模型中,CDK1和cyclinB1是BMP的訊息透過非SMAD傳遞路徑下游之重要的目標基因。我們的結論指出BMP4訊息傳遞途徑具有成為肝癌的新治療標靶的潛力。以長遠的觀點來說,如果可以瞭解BMP4訊息傳遞網的模式與它在肝癌腫瘤的生物性角色,毫無疑問地,除了可以提供另一種理想的治療途徑外,也能作為協助診斷的依據以及肝癌發生的預測指標。
Abstract
Hepatocarcinoma cancer (HCC) is one the most common visceral malignancies in Taiwan, which has a very high incidence and a devastatingly poor prognosis. BMP4, belonging to the TGF-β super-family of proteins is a multifunctional cytokine, known to exert its biological effects through SMAD and non-SMAD dependent pathways and is also known to be involved in human carcinogenesis. However, the effects of the BMP4 signaling in liver carcinogenesis are not yet clearly defined. In this study, we first demonstrate that BMP4 and its receptor, BMPR1A, are over-expressed in a majority of primary HCC and promote the growth and migration of HCC cell lines in vitro. We also further identify that BMP4 can induce HCC CDK1 and cyclinB1 up-regulation to accelerate cell cycle progression. Our study indicates that the induction of HCC cell proliferation is independent on the SMAD signaling pathway, since Smad4 knockdown of BMP4 induced HCC cell lines still leads to the up-regulation of CDK1 and cyclinB1 expression in HCC. Using MEK kinase selective inhibitors, the induction of CDK1 and cyclinB1 mRNA and protein were shown to be dependent on the activation of MEK/ERK signaling. In vivo xenograft studies confirmed that the BMPR1A- knockdown cells were significantly less tumorigenic than control groups. Taken together, our findings show that the up-regulation of BMP4 and BMPR1A in HCC promote the proliferation and metastasis of HCC cells and that CDK1 and cyclinB1 are important, SMAD-independent molecular targets in BMP4 signaling pathways during the HCC tumorigenesis. We propose here that BMP4 signaling pathways may have potential as new therapeutic targets, in HCC treatment.
目次 Table of Contents
Abstract in Chinese P. I
Abstract in English P.II
Abbreviations P.III
Introduction P.1
Materials and Methods P.6
Results P.13
BMP4 and BMPR1A are up-regulated, while BMPR1B is down-regulation in HCC 13
BMP4 induced CDK1 and cyclinB1 expression to promote HCC proliferation 14
Smad4 deficiency leads to increased expression of CDK1 and cyclinB and enhances cell proliferation, especially BMP4 presence 15
Inhibition of MEK/ERK signaling pathway efficiently decreases BMP4 mediated the increased expression of CDK1 and cyclinB1 in HCC 17
BMPR1A-knockdown HCC cells are significantly less tumorigenic in vitro and in vivo xenograft studies 17
BMP4 type IA receptor knockdown or inhibits of MEK/ERK signaling pathway attenuated BMP4 induced HCC cells migration 18
Discussion P.20
Figures and Tables P.25
References P.42
Appendix P.53
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