請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/31013
標題: | 猴病毒四十型T/t-common蛋白質特異性地誘導HER2/neu大量表現的癌細胞走向細胞凋亡 SV40 T/t-Common Polypeptide Specifically Induces Apoptosis in Human Cancer Cells that Overexpress HER2/neu |
作者: | Chun-Chiang Wen 溫俊強 |
指導教授: | 王萬波 |
關鍵字: | 人類表皮生長因子接受器,猴病毒四十型,大T小T共同區域,細胞凋亡,腫瘤抑制, simian virus 40 (SV40),T/t-common,HER2/neu,apoptosis,tumor suppression, |
出版年 : | 2007 |
學位: | 博士 |
摘要: | HER2/neu屬於表皮生長因子接受器家族(epidermal growth factor receptor family;EGF receptor family)的一員。HER2/neu基因在許多人類癌症中時常有放大(amplification)或過度表現(overexpression)的現象,目前已知HER2/neu可以傳遞數個不同的信號路徑,這些路徑導致HER2/neu具有強大的致癌能力,因此,HER2/neu被認為是治療癌症的標的之一。
我們實驗室之前的研究證實了,SV40 T/t-common可以抑制HER2/neu啟動子的活性,並且可以抑制HER2/neu-overexpressing的卵巢癌細胞SK-OV-3中HER2/neu的表現量及其轉形活性。 在本論文中,我們進一步發現,T/t-common可以專一性的造成HER2/neu-overexpressing的癌細胞走向細胞凋亡,但是卻不會影響HER2/neu low-expressing的癌細胞或非轉形細胞。而T/t-common造成HER2/neu-overexpressing的癌細胞走向細胞凋亡,可能是透過抑制HER2/neu的表現,影響了細胞內MEK-ERK訊息傳遞,造成Bcl-2及Bcl-XL表現量下降,而導致細胞走向細胞凋亡。另外,我們也發現,T/t-common可以專一性的抑制HER2/neu-overexpressing的癌細胞在柔軟瓊脂產生聚落的能力,T/t-common亦具有抑制新生血管形成的潛力。以上結果顯示,T/t-common具有用於治療HER2/neu-overexpressing癌症的潛力。同時在本論文中,增加細胞中p300的表現量,仍然無法回復被T/t-common所抑制的HER2/neu啟動子的活性,因此,T/t-common並不是透過抑制p300而抑制了HER2/neu啟動子的活性。 HER2/neu gene (also known as erbB-2) is a proto-oncogene which belongs to the epidermal growth factor receptor family. It is overexpressed in many human cancers, including breast, lung, ovary, pancreas, gastric, and oral cancers. Overexpression of HER2/neu is associated with poor clinical outcome, including short survival time and short time to relapse. HER2/neu-overexpressing cancer cells usually have higher potential to proliferate, metastasize, induce angiogenesis, and resist chemotherapeutic agents. Inhibition of HER2/neu can lead to suppression of the tumorigenicity of HER2/neu-overexpressing cancer cells. Therefore HER2/neu gene is a suitable target for cancer treatment. Previously we reported that simian virus 40 (SV40) T/t-common polypeptide, which contains the N-terminal common domain of SV40 large T and small t antigens, can repress HER2/neu expression and consequently suppress the tumorigenic potential of the HER2/neu-overexpressing ovarian carcinoma cells. Here we report that T/t-common could specifically induce apoptosis in HER2/neu-overexpressing human cancer cell lines but not in non-transformed cell lines and HER2/neu low-expressing human cancer cell lines. T/t-common’s ability to induce apoptosis in HER2/neu-overexpressing cancer cells was derived from its ability to inhibit HER2/neu, because re-expression of a large amount of HER2/neu could block apoptosis induced by T/t-common. T/t-common expression in HER2/neu-overexpressing SK-OV-3 cancer cells led to down-regulation of Bcl-2 and Bcl-XL, and overexpression of Bcl-2 could inhibit T/t-common’s ability to induce apoptosis in these cells. Therefore, T/t-common’s apoptosis-inducing activity is related to its ability to inhibit Bcl-2 expression in HER2/neu-overexpressing cancer cells. Consistent with T/t-common’s apoptosis-inducing activity, we found that T/t-common could specifically inhibit the soft-agarose colony-forming ability of the HER2/neu-overexpressing human cancer cell lines but not that of the HER2/neu low-expressing human cancer cell lines. Finally, we demonstrated that T/t-common could specifically sensitize HER2/neu-overexpressing human cancer cell lines, but not HER2/neu low-expressing human cancer cell lines, to chemotherapeutic agent etoposide. Together, these data suggest that T/t-common alone or in combination with chemotherapy may provide a new approach for treatment of cancers that overexpress HER2/neu. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/31013 |
全文授權: | 有償授權 |
顯示於系所單位: | 微生物學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-96-1.pdf 目前未授權公開取用 | 2.54 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。