MicroRNA-708啟動子的甲基化促進乳癌的進程與轉移

簡易檢索 / 詳目顯示

回結果列表

研究生：	潘彥茹 Pan, Yan-Ru.
論文名稱：	MicroRNA-708啟動子的甲基化促進乳癌的進程與轉移 Epigenetic suppression of microRNA-708 promotes breast cancer progression and metastasis
指導教授：	林愷悌 Lin, Kai-Ti
口試委員:	鄭世進 Cheng, Shih-Chin 王群超 Wang, Chun-Chao
學位類別：	碩士 Master
系所名稱：	生命科學暨醫學院 - 生物科技研究所 Biotechnology
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	42
中文關鍵詞：	乳癌、轉移、表觀遺傳學修飾、去氧核糖核酸甲基化、組蛋白-離氨酸N-甲基轉移酶
外文關鍵詞：	epigenetic modifications, microRNA-708
相關次數：	點閱：3 下載：0
分享至:	分享至facebook 分享至twitter

查詢本校圖書館目錄查詢臺灣博碩士論文知識加值系統勘誤回報

乳腺癌在女性統計數據中是造成癌症死亡的第二大原因。在乳癌症的患者中，轉移與否與癌症的死亡率有非常大的關連性。迄今為止，還沒有可用於治療乳腺癌轉移的標靶療法。我們先前的研究表明，糖皮質激素（GCs）可通過誘導microRNA-708的表現因此抑制卵巢癌的遠端轉移。在此篇研究，我們深入探討糖皮質激素用於治療轉移性乳腺癌的潛力。我們觀察到microRNA-708啟動子區域在轉移性乳腺癌細胞中會透過DNA甲基化和組蛋白甲基化的方式導致表觀遺傳學的改變，進而抑制基因的表現。而共同給予糖皮質激素與DNA去甲基化劑─阿扎胞苷，可以顯著增加microRNA-708的表達，偕同抑制腫瘤的生長與轉移。總體而言，我們的數據揭示了使用糖皮質激素與表觀遺傳藥物抑制乳腺癌的進展和轉移的治療策略。

Breast cancer is the second leading cause of cancer death in women and cancer metastasis are responsible for almost 90% of breast cancer-related deaths. To date, there is no targeted therapy available in treating breast cancer metastasis. Previous study indicates that glucocorticoids (GCs) suppress cancer metastasis in ovarian cancer through induction of microRNA-708. Here we propose to investigate the therapeutic potential of GCs in treating metastatic breast cancer. We observe that microRNA-708 promoter region is epigenetically silenced by both DNA methylation and histone methylation among metastatic breast cancer cells. Co-treatment of GCs, together with DNA-demethylation agents, decitabine (5-aza-2'-deoxycytidine), significantly increases the expression of microRNA-708, leading to the synergistic suppression of tumor growth. Overall, our data reveal a potential strategy of using GCs together with the epigenetic drug to suppress breast cancer progression and metastasis.

摘要.....................................................i
Abstract................................................ii
致謝....................................................iii
Table of Contents.......................................iv
Table of Figures........................................vi
Introduction............................................1
1.1    Breast Cancer...................................1
1.1.1    Treatment options for metastatic breast cancer..3
1.2    Epigenetics.....................................4
1.3    MicroRNA........................................6
1.4    Decitabine......................................6
1.5    Dexamethasone...................................7
Motivation and aims.....................................8
Materials and Methods..................................10
3.1    Cell culture and transfection..................10
3.2    Western blot analysis..........................11
3.3    Quantitative real-time RT-PCR..................12
3.4    Mouse orthotropic metastasis model.............14
3.5    Bisulfite sequencing...........................15
3.6    Chromatin Immunoprecipitation assay............18
Results    ...............................................23
4.1    MicroRNA-708 is downregulated in breast cancer.23
4.2    The promoter region of microRNA-708 highly methylated and associated with patient survival.......................23
4.3    Knockdown of EZH2 induces expression of microRNA-708..24
4.4   Knockdown of EZH2 increases methylation level in the promoter region of microRNA-708.................................25
4.5  The promoter region of microRNA-708 is bound to methylated H3K27 and H3K4    .......................................25
4.6    Co-treatment of DEX and Decitabine suppresses breast cancer metastasis in the mouse model..........................26
4.7  Co-treatment of DEX and Decitabine induce expression of microRNA-708 in mouse model..................................................27
Conclusion.............................................29
Discussion.............................................30
Reference..............................................41

                                

1. Libson, S. and M.J.I.r.o.p. Lippman, A review of clinical aspects of breast cancer. 2014. 26(1): p. 4-15.
2. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2018. 2018. 68(1): p. 7-30.
3. TAIWAN, H.P.A.M.O.H.A.W., CANCER REGISTRY ANNUAL REPORT. 2016.
4. Sotiriou, C. and L.J.N.E.J.o.M. Pusztai, Gene-expression signatures in breast cancer. 2009. 360(8): p. 790-800.
5. Mauri, D., et al., Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. 2006. 98(18): p. 1285-1291.
6. André, F., et al., Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. 2014. 15(6): p. 580-591.
7. Wilcken, N. and R.J.E.J.o.C. Dear, Chemotherapy in metastatic breast cancer: a summary of all randomised trials reported 2000–2007. 2008. 44(15): p. 2218-2225.
8. Hartsell, W.F., et al., Randomized trial of short-versus long-course radiotherapy for palliation of painful bone metastases. 2005. 97(11): p. 798-804.
9. Harris, J.R., et al., Diseases of the Breast. 2012: Lippincott Williams & Wilkins.
10. Seyfried, T.N. and L.C.J.C.r.i.o. Huysentruyt, On the origin of cancer metastasis. 2013. 18(1-2): p. 43.
11. Handy, D.E., R. Castro, and J.J.C. Loscalzo, Epigenetic modifications: basic mechanisms and role in cardiovascular disease. 2011. 123(19): p. 2145-2156.
12. Moosavi, A. and A.M.J.I.b.j. Ardekani, Role of epigenetics in biology and human diseases. 2016. 20(5): p. 246.
13. Kleer, C.G., et al., EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. 2003. 100(20): p. 11606-11611.
14. Weikert, S., et al., Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. 2005. 16(2): p. 349-353.
15. Varambally, S., et al., The polycomb group protein EZH2 is involved in progression of prostate cancer. 2002. 419(6907): p. 624.
16. Kim, Y.-I.J.T.J.o.n., Nutritional epigenetics: impact of folate deficiency on DNA methylation and colon cancer susceptibility. 2005. 135(11): p. 2703-2709.
17. Gharibiyan, A., et al., Serum/plasma DNA methylation pattern and early detection of breast cancer. 2015. 4(2): p. 120.
18. Yoo, K.H. and L.J.I.j.o.b.s. Hennighausen, EZH2 methyltransferase and H3K27 methylation in breast cancer. 2012. 8(1): p. 59.
19. Bartel, D.P. and C.-Z.J.N.r.g. Chen, Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. 2004. 5(5): p. 396.
20. Naeini, M.M. and A.M.J.A.j.o.m.b. Ardekani, Noncoding RNAs and cancer. 2009. 1(2): p. 55.
21. MacFarlane, L.-A. and P.J.C.g. R Murphy, MicroRNA: biogenesis, function and role in cancer. 2010. 11(7): p. 537-561.
22. Pratt, A.J. and I.J.J.J.o.B.C. MacRae, The RNA-induced silencing complex: a versatile gene-silencing machine. 2009. 284(27): p. 17897-17901.
23. Takahashi, R.-u., H. Miyazaki, and T.J.C. Ochiya, The roles of microRNAs in breast cancer. 2015. 7(2): p. 598-616.
24. Glover, A.B. and B.J.C.t.r. Leyland-Jones, Biochemistry of azacitidine: a review. 1987. 71(10): p. 959-964.
25. Berger, S.A., et al., Molecular genetic analysis of glucocorticoid and mineralocorticoid signaling in development and physiological processes. 1996. 61(4): p. 236-239.
26. Shiratsuchi, T., H. Ishibashi, and K.J.J.o.c.p. Shirasuna, Inhibition of epidermal growth factor‐induced invasion by dexamethasone and AP‐1 decoy in human squamous cell carcinoma cell lines. 2002. 193(3): p. 340-348.
27. Piette, C., et al., The dexamethasone-induced inhibition of proliferation, migration, and invasion in glioma cell lines is antagonized by macrophage migration inhibitory factor (MIF) and can be enhanced by specific MIF inhibitors. 2009. 284(47): p. 32483-32492.
28. Zheng, Y., et al., Contrary regulation of bladder cancer cell proliferation and invasion by dexamethasone-mediated glucocorticoid receptor signals. 2012. 11(12): p. 2621-2632.
29. Lin, K.-T., et al., Glucocorticoids mediate induction of microRNA-708 to suppress ovarian cancer metastasis through targeting Rap1B. 2015. 6: p. 5917.
30. Ryu, S., et al., Suppression of miRNA-708 by polycomb group promotes metastases by calcium-induced cell migration. 2013. 23(1): p. 63-76.
31. Baer, C., et al., Epigenetic silencing of miR‐708 enhances NF‐κB signaling in chronic lymphocytic leukemia. 2015. 137(6): p. 1352-1361.
32. Ramchandani, D., et al., Nanoparticle delivery of miR-708 mimetic impairs breast cancer metastasis. 2019. 18(3): p. 579-591.

簡易檢索 / 詳目顯示

相關論文