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標題: | 間質蛋白酶在表皮生長因子所誘發的大腸癌細胞侵襲移動力中扮演角色 Matriptase is involved in EGF-induced colorectal cancer cell invasion |
作者: | Sheng-Ta Chung 鍾昇達 |
指導教授: | 李明學(Ming-Shyue Lee) |
關鍵字: | 表皮生長因子,間質蛋白酶,TMPRSS2,大腸癌,轉移, EGFR,matriptase,TMPRSS2,colorectal cancer,metastasis, |
出版年 : | 2013 |
學位: | 碩士 |
摘要: | 失調的致癌基因訊息或細胞外緣的蛋白分解酶作用被認為與癌症的侵襲和轉移是有著莫大關係。在本篇研究中,我們利用一組人類大腸癌惡化轉移細胞模式,包括KM12C, KM12-L4, KM12-SM細胞,探討表皮生長因子受器(EGFR)、及兩種第二型嵌膜絲氨酸蛋白酶[間質蛋白酶 (Matriptase)和TMPRSS2]在大腸癌細胞侵襲中扮演的角色。我們的結果指出表皮生長因子受器的蛋白質表達量及其磷酸化程度、間質蛋白酶及TMPRSS2的活性,在具高轉移侵襲力的大腸癌KM-L4和KM12-SM細胞中,均明顯的增加,並與細胞的侵襲能力,呈現正相關。利用基因大量表達或剔除的實驗,結果發現表皮生長因子受器、間質蛋白酶及TMPRSS2,均參與EGF所誘發增加的大腸癌細胞侵襲能力。當大量表達TMPRSS2在大腸癌細胞時,間質蛋白酶的活性會隨之增加,但過量表達間質蛋白酶卻不會造成TMPRSS2的活化。此結果顯示在大腸癌細胞中TMPRSS2是間質蛋白酶的上游調控分子。同時,從抑制劑的實驗發現,EGF可以透過活化PI3K/AKT訊息,進而活化間質蛋白酶及促進大腸癌細胞侵襲力的上升。綜合上述的結果,發現在大腸癌細胞中,表皮生長因子訊息可經由PI3K/AKT或驅動TMPRSS2的活化,進而促進間質蛋白酶活性的上升,造成癌細胞移動侵襲能力的增加。 Dysregulation of oncogenic signaling or proteolysis on cell surface has been proposed to play an important role in cancer cell invasion and metastasis. In this study, I delineated the roles of EGFR, matriptase and TMPRSS2 in colorectal cancer cell invasion, using a human colorectal cancer metastasis progression model (KM12C, KM12-L4 and KM12-SM cells). KM12-L4 and KM12-SM cells are two cell lines established from KM12C cells, and exhibited higher invasion and metastasis potentials than KM12C cells. My results showed that the protein and tyrosine phosphorylation levels of EGFR were dramatically increased in KM12-L4 and KM12-SM cells in comparison of KM12C cells, which were concurrent with the high levels of activated matriptase and TMPRSS2. With overexpression or knockdown approaches, the results indicated that EGFR, matriptase and TMPRSS2 were involved in colorectal cancer cell invasion. Moreover, my data further indicated that EGF could stimulate colorectal cancer cell invasion, matriptase and TMPRSS2 activation. TMPRSS2 overexpression could increase the activated levels of matriptase while matriptase overexpression had no effect on TMPRSS2, suggesting a proteolytic cascade from TMPRSS2 to matriptase. In addition, EGF-induced matriptase activation was at least partly via PI3K but not MEK/Erk1/2 signaling. Taken together, the data indicate that EGFR signaling can be through PI3K/AKT or TMPRSS2 to induce matriptase activation, leading to increasing colorectal cancer cell invasion. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/61445 |
全文授權: | 有償授權 |
顯示於系所單位: | 生物化學暨分子生物學科研究所 |
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