絲裂原活化蛋白激酶去磷酸酶在乳癌細胞惡性度中所扮演之角色

Role of Mitogen Protein Kinase Phosphatase-1 in Breast Cancer Cells Malignancy

鄭永彥(Yung-Yen Cheng)

指導教授 ： 李宏謨

臺北醫學大學/醫學院/醫學科學研究所/碩士(2009年)

摘要

乳癌為現今全球女性的主要死因，在過去研究指出，（Mitogen activated protein kinase phosphatase-1, MKP-1）在乳癌惡性度中扮演重要角色。本實驗比較不同細胞株（MCF-7與MDA-MB-231）MKP-1的表現後證實與惡性度呈正相關。本論文證實MKP-1調控乳癌惡性度。MCF-7細胞（MKP-1表現量低的細胞）中穩定表現MKP-1，可改變腫瘤細胞的上皮-間質轉化（epithelial to mesencymal transition, EMT）現象；降低鈣黏著素E（E-cadherin）的RNA及蛋白表現量。相對地，在高惡性度的MDA-MB-231細胞株（MKP-1表現量高）中穩定表現特定小髮夾RNA（Short hairpin RNA. shRNA）或以triptolide處理以抑制MKP-1的表現，可降低波形蛋白（vimentin）的表現以及細胞的惡性度。最後本實驗證實在抗tamoxifen的MCF-7細胞中，MKP-1於細胞自噬作用及上皮-間質轉化中扮演重要角色，此現象與臨床現象中發現對tamoxifen產生抗性的病患往往伴隨癌症轉移現象一致。此外本實驗證明triptolide抑制MKP-1可導致乳癌細胞的惡性度及波形蛋白降低；此結果顯示在乳癌治療中，MKP-1可能可作為治療的分子標靶，而triptolide或許有潛力成為乳癌治療用藥的佐劑。

關鍵字

MKP-1 ； 乳癌

並列摘要

Breast cancer is a major cause of mortality in female worldwide. Mitogen activated protein phosphatase-1 (MKP-1) has been shown to play a critical role in the malignancy of breast cancer. In this study, we first demonstrated that MKP-1 expression correlated well with metastastic capacity by comparing two breast cancer cell lines (MCF-7 and MDA-MB231). We determined whether MKP-1 regulates malignancy in breast cancer. The forced ectopic expression of MKP-1 in MCF-7 cells (low MKP-1 expression) altered the epithelial to mesencymal transition (EMT) state, decreasing E-cadherin RNA and protein levels and enhancing cell metastasis in vitro. In contrast, stable expression of specific shRNA to knockdown MKP-1 expression or treatment with triptolide, a pharmacological blocker of MKP-1, in highly metastasis type MDA-MB-231 cells (with high MKP-1 expression) decreased vimentin expression and cell metastasis. Finally, we demonstrated that MKP-1 plays a major role in autophagy and epithelial-to-mesenchymal-like transition (EMT) in tamoxifen resistance MCF-7 cells. These observations are consistent with clinical observations in patients with tamoxifen resistance and accompanied metastasis. In addition, we provide evidence that triptolide-reduced MKP-1 expression lead to decreased breast cancer cell metastasis and vimentin expression. These data suggest that MKP-1 might be used as therapeutic target and triptolide may be used as an adjuvant drug for breast cancer therapy.

並列關鍵字

MKP-1 ； breast cancer

參考文獻

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