探討新穎Btk酪氨酸激酶抑制劑 CTN06 對乳癌細胞之影響

Taipei Medical University Institutional Repository > 醫學科技學院 > 醫學檢驗暨生物技術學系所 > 博碩士論文 > Item 987654321/54091

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題名:	探討新穎Btk酪氨酸激酶抑制劑 CTN06 對乳癌細胞之影響 CTN06: a novel Bruton's tyrosine kinase inhibitor for the treatment of breast malignancies
作者:	盧彥蓉 Lu, Yen-Jung
關鍵詞:	乳癌;非受體型酪胺酸激酶
日期:	2013-07-20
上傳時間:	2018-11-16 12:18:43 (UTC+8)
摘要:	BTK( Bruton's tyrosine kinase)家族是屬於非受體型酪胺酸激酶 (Non-receptor tyrosine kinase)，參與了調節細胞多種功能，如：細胞的生長、存活、遷移等。BTK的高度表現在惡性脊隨病變中並以被顯示為致癌基因。過去研究發現BTK只單獨表現在B cell中，在實體腫瘤中的功能角色至今尚未完全釐清。在本研究中，我們實驗結果清楚證實BTK在數種乳癌細株胞與癌症組織中有過量表現的情況，證明了過度表現的BTK的確有助於乳癌的發生。特別是在侵犯能力強的乳癌細胞株中表現更是明顯。這些結果讓我們進一步探討BTK於侵犯性乳癌細胞中之扮演的角色。因此利用wound-healing 方法分析CTN06抑制劑或BTK小分子干擾對三陰性乳癌細胞株MDAMB231轉移能力的影響。此外，利用西方墨點法分析EMT標記的表現及以光學顯微鏡觀察細胞型態的改變。證實，當BTK被CTN06抑制或BTK小分子干擾後，除了改變MDAMB231細胞mesenchymal-like的型態，也影響了EMT標記蛋白的表現，例如：E-cadherin表現量上升及vimentin 、Slug 、Twist表現量下降。同時，在MDAMB231細胞中合併使用CTN06 及 Paclitaxel化療藥物也達到協同作用的反應，因此抑制BTK的活性不論是單獨使用CTN06或是合併使用化療藥物的治療都可以有效達到抑制惡性乳癌細胞的生長及轉移能力。本實驗也是首先證明CTN06抑制劑有效抑制BTK的表現進而抑制乳癌細胞的生長及轉移能力。 Btk family kinases are non-receptor tyrosine kinases which are involved in the regulation of diverse cellular processes such as growth, survival and migration. Btk upregulation has been attributed to the oncogenesis of myeloid malignacies. However its functions in solid tumors have not been explored due to its prominent expression in B cells. This study was conducted to investigate the role of Btk in the regulation of epithelial to mesenchymal transition (EMT) in human breast carcinoma. Btk inhibition by CTN06 (a specific Btk family kinase inhibitor) or small interfering RNA (shRNA) was carried out in metastatic triple-negative MDA-MB-231 cells. Cell migration was analyzed by wound-healing assay. The protein levels of EMT markers and transcription factors were evaluated by Western blot analysis, respectively. Morphological changes in Btk modified cells were observed by light microscope. Btk suppression by CTN06 or shRNA reversed the mesenchymal-like phenotype in MDA-MB-231 cells. E-cadherin was upregulated in MDA-MB-231 cells after Btk suppression, whereas vimentin was downregulated. Master EMT regulators including Slug and Twist were downregulated in Btk-silenced MDA-MB-231 cells, while Snail was unchanged. Furthermore, combined treatment with CTN06 and Paclitaxel exerted synergistic effects in MDA-MB-231 cells, suggesting that the inhibition of Btk kinase activity by CTN06 alone or in combination with other agents can be a strategy to target malignant breast cancer. Collectively, we demonstrated for the first time that Btk suppression by CTN06 or shRNA not only suppressed tumor growth but also EMT in metastatic breast cancer cells MDA-MB-231.
描述:	碩士指導教授-何元順教授共同指導教授-葉淇臺助理教授委員-蔡麗玉教授
資料類型:	thesis
顯示於類別:	[醫學檢驗暨生物技術學系所] 博碩士論文

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