進階搜尋


 
系統識別號 U0026-2308201713143500
論文名稱(中文) 缺氧誘導MXI1在子宮內膜異位症中的功能探討
論文名稱(英文) The functional role of hypoxia-induced MXI1 in endometriosis
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 105
學期 2
出版年 106
研究生(中文) 陳一誠
研究生(英文) Yi-Cheng Chen
電子信箱 j6569642@yahoo.com.tw
學號 S36044070
學位類別 碩士
語文別 英文
論文頁數 66頁
口試委員 指導教授-吳孟興
口試委員-蔡少正
口試委員-林赫
中文關鍵字 子宮內膜異位症  缺氧  細胞增生  抗細胞凋亡 
英文關鍵字 Endometriosis  hypoxia  MXI1  cell proliferation  anti-apoptosis 
學科別分類
中文摘要 子宮內膜異位症,泛指子宮內膜腺體及基質細胞生長於子宮外,是一種極為常見的婦女疾病,並大大影響了病患的生活品質。子宮內膜異位症被廣泛接受是起因於子宮內膜組織遭遇了經血逆流的壓力,在此過程中,剝落下來之子宮內膜組織因獲得細胞抗凋亡及細胞增生能力,以至於這些細胞能夠生存在像是缺氧、細胞不貼附、以及營養不足等許多逆境中。缺氧在子宮內膜異位症中調控許多細胞生長反應,像是發炎反應、類固醇形成、血管新生等。但在子宮內膜異位症中,缺氧是否提高細胞增生及抗凋亡能力的機制是尚未被闡明的。因此,我們假設在經血逆流過程中,剝落下來的子宮內膜原位基質細胞會遭遇到缺氧逆境、進而提高細胞抗凋亡及細胞增生能力。首先,經由西方墨點分析凋亡蛋白酶三,以及溴化去氧尿苷的滲入培養來偵測增生中細胞等實驗下,我們證實了在缺氧及缺氧誘導物DMOG的前處理後,子宮內膜原位基質細胞不但對於喜樹鹼所引發的細胞凋亡能力顯著下降,並且其細胞增生能力顯著提升,本結果支持我們提出之缺氧誘導子宮內膜原位基質抗凋亡及細胞增生現象之假說。為了更進一步探討在基質細胞中有什麼因子調控缺氧誘導的保護作用,我們利用GEO生物資訊分析成對的子宮內膜原位及異位基質細胞中的基因表現 (GSE7305),發現MXI1這個抗凋亡轉錄調控因子在子宮內膜異位組織的表現量是上升的。而利用定量聚合酶連鎖反應以及西方墨點分析下,我們首次證實了MXI1的信使核糖核酸以及蛋白質量確實在人類子宮內膜異位基質細胞中表現上升。我們更進一步利用生物資訊工具The Best探討人類MXI1基因內部的結合元件,釐清其啟動子區域內具有兩個典型的缺氧誘導元件,可被缺氧誘導因子所接合。在藉由缺氧及DMOG的培養下,子宮內膜原位基質細胞的MXI1信使核糖核酸以及蛋白質的表現量上升。然而,缺氧前處理的子宮內膜原位基質細胞其細胞增生能力上升現象在給予微小干擾MXI1核苷酸後是被抑制的。綜上所述,缺氧誘導MXI1在子宮內膜異位症致病機轉中可能是一個重要的細胞增生調控因子。
英文摘要 Endometriosis, defined as the presence of endometrial glandular and stromal tissues outside of the uterine cavity, is one of the most common gynecological diseases and greatly reduces the quality of patients’ life. It is well-accepted that ectopic endometriotic tissues are derived and established from the retrograded endometrial fragments. During retrogradation, the cast-off endometrial tissues have to gain the capacities of anti-apoptosis and proliferation to survive under numerous stresses such as hypoxia, cell detachment, and nutritional deprivation. Hypoxia modulates several cellular processes involved in the pathological developments of endometriosis such as inflammation, steroidogenesis, and angiogenesis, but it still remains elusive whether hypoxia indeed promotes anti-apoptosis and proliferation in endometriosis. Therefore, we hypothesized that the hypoxic stress promotes anti-apoptosis and cell proliferation in eutopic stromal cells during retrograded menstruation. First, the western blotting results of caspase 3 activation and the BrdU incorporation assay, which directly detects proliferating cells showed that pretreatment with hypoxia and hypoxia mimetic Dimethyloxaloylglycine (DMOG) in eutopic stromal cells significantly not only reduced camptothecin (CPT)-induced apoptosis but also promoted cell proliferation, supporting the hypothesis that hypoxia induces anti-apoptosis and proliferation in eutopic stromal cells. To further investigate what factor mediates the hypoxia-induced protective effect in the stromal cells, we analyzed the differentially expressed genes in paired eutopic and ectopic stromal cells by using Gene Expression Omnibus (GEO) data (GSE7305), and found that MAX interactor 1, dimerization protein (MXI1), an anti-apoptotic transcription factor, was elevated in ectopic stromal cells. By using quantitative PCR and western blotting, we first confirmed that MXI1 is elevated in human ectopic stromal cells compared to the paired eutopic stromal cells. Moreover, the Binding Elements Searching Tools (The BEST) identified two typical hypoxia-responsive elements (HREs), the DNA sequence recognized by hypoxia-inducible factors, in human MXI1 promoter. Treatment with hypoxia or DMOG in eutopic stromal cells induced the expression of MXI1 mRNA and protein. Nevertheless, the hypoxia pretreatment-induced cell proliferation was suppressed by MXI1 knockdown in eutopic stromal cells. Taken together, the evidence suggests that hypoxia-induced MXI1 may be an important regulator for cell proliferation during the pathogenesis of endometriosis.
論文目次 Abstract I
中文摘要 III
誌謝 V
Table of Content VII
Introduction 1
Material & Methods 10
Clinical patients 10
Isolation of stromal cells 10
Cell culture and hypoxia treatment 11
DNA damage-induced apoptosis 12
RNA isolation, reverse transcription and quantitative real-time PCR (RT-qPCR) 12
Western blotting analysis 13
Transfection, RNA interference, and overexpression construct 13
BrdU incorporation assay 14
Statistical analysis 14
Results 16
Hypoxia pretreatment protected eutopic endometrial stromal cells from CPT-induced apoptosis 16
Hypoxia pretreatment promoted cell proliferation in eutopic endometrial stromal cells 16
MXI1 was elevated in human endometriotic tissues compared with normal endometrium 19
Upregulation of MXI1 was induced by hypoxia treatment in eutopic endometrial stromal cells 26
MXI1-SRβ was not involved in hypoxia-suppressed apoptosis in eutopic endometrial stromal cells 26
Hypoxia-induced cell proliferation was inhibited by siMXI1 knockdown in eutopic endometrial stromal cells 32
Discussion 38
References 43
Appendix 54
1. Primer list 54
2. The siRNA oligonucleotides sequences 54
3. Antibodies 55
4. Reagents and buffers used in cell culture 56
5. Reagents used in cell treatment 57
6. Reagents and buffers used in RNA isolation 57
7. Reagents and buffers used in PCR 58
8. Reagents and buffers used in Western Blotting 58
9. Reagents and buffers used in BrdU incorporation assay 60
10. Protocols 60
參考文獻 1. Olive DL, Schwartz LB. Endometriosis. N Engl J Med 1993; 328: 1759-1769.
2. Giudice LC, Kao LC. Endometriosis. Lancet 2004; 364: 1789-1799.
3. Wang KC, Chang WH, Lee WL, et al. An increased risk of epithelial ovarian cancer in Taiwanese women with a new surgico-pathological diagnosis of endometriosis. BMC Cancer 2014; 14: 831.
4. Wu MH, Shoji Y, Chuang PC, et al. Endometriosis: disease pathophysiology and the role of prostaglandins. Expert Rev Mol Med 2007; 9: 1-20.
5. Harada T. Dysmenorrhea and endometriosis in young women. Yonago Acta Med 2013; 56: 81-84.
6. Wu MH, Lu CW, Chuang PC, et al. Prostaglandin E2: the master of endometriosis? Exp Biol Med (Maywood) 2010; 235: 668-677.
7. Bulletti C, Coccia ME, Battistoni S, et al. Endometriosis and infertility. J Assist Reprod Genet 2010; 27: 441-447.
8. Bulun SE. Endometriosis. N Engl J Med 2009; 360: 268-279.
9. Tsai SJ, Wu MH, Lin CC, et al. Regulation of steroidogenic acute regulatory protein expression and progesterone production in endometriotic stromal cells. J Clin Endocrinol Metab 2001; 86: 5765-5773.
10. Wu MH, Lu CW, Chang FM, et al. Estrogen receptor expression affected by hypoxia inducible factor-1alpha in stromal cells from patients with endometriosis. Taiwan J Obstet Gynecol 2012; 51: 50-54.
11. Wu MH, Sun HS, Lin CC, et al. Distinct mechanisms regulate cyclooxygenase-1 and -2 in peritoneal macrophages of women with and without endometriosis. Mol Hum Reprod 2002; 8: 1103-1110.
12. Wu MY, Ho HN. The role of cytokines in endometriosis. Am J Reprod Immunol 2003; 49: 285-296.
13. Wu MH, Wang CA, Lin CC, et al. Distinct regulation of cyclooxygenase-2 by interleukin-1beta in normal and endometriotic stromal cells. J Clin Endocrinol Metab 2005; 90: 286-295.
14. Kao AP, Wang KH, Long CY, et al. Interleukin-1beta induces cyclooxygenase-2 expression and promotes the invasive ability of human mesenchymal stem cells derived from ovarian endometrioma. Fertil Steril 2011; 96: 678-684.e671.
15. Sedger LM, McDermott MF. TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants – past, present and future. Cytokine Growth Factor Rev 2014; 25: 453-472.
16. Kim YA, Kim JY, Kim MR, et al. Tumor necrosis factor-alpha-induced cyclooxygenase-2 overexpression in eutopic endometrium of women with endometriosis by stromal cell culture through nuclear factor-kappaB activation. J Reprod Med 2009; 54: 625-630.
17. Oku H, Tsuji Y, Kashiwamura SI, et al. Role of IL-18 in pathogenesis of endometriosis. Hum Reprod 2004; 19: 709-714.
18. Vercellini P, Vigano P, Somigliana E, et al. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol 2014; 10: 261-275.
19. Ugur M, Turan C, Mungan T, et al. Endometriosis in association with mullerian anomalies. Gynecol Obstet Invest 1995; 40: 261-264.
20. Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 1927; 14: 422-469.
21. Hsiao KY, Lin SC, Wu MH, et al. Pathological functions of hypoxia in endometriosis. Frontiers in bioscience (Elite edition) 2015; 7: 309-321.
22. Leyendecker G, Herbertz M, Kunz G, et al. Endometriosis results from the dislocation of basal endometrium. Hum Reprod 2002; 17: 2725-2736.
23. Bristow RG, Hill RP. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 2008; 8: 180-192.
24. Lee JW, Bae SH, Jeong JW, et al. Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp Mol Med 2004; 36: 1-12.
25. Wenger RH. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J 2002; 16: 1151-1162.
26. Semenza GL. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol 2014; 9: 47-71.
27. Hsiao KY, Chang N, Lin SC, et al. Inhibition of dual specificity phosphatase-2 by hypoxia promotes interleukin-8-mediated angiogenesis in endometriosis. Hum Reprod 2014; 29: 2747-2755.
28. Filippi I, Carrarelli P, Luisi S, et al. Different Expression of Hypoxic and Angiogenic Factors in Human Endometriotic Lesions. Reprod Sci 2016; 23: 492-497.
29. Lin SC, Wang CC, Wu MH, et al. Hypoxia-induced microRNA-20a expression increases ERK phosphorylation and angiogenic gene expression in endometriotic stromal cells. J Clin Endocrinol Metab 2012; 97: E1515-1523.
30. Xiong W, Zhang L, Xiong Y, et al. Hypoxia Promotes Invasion of Endometrial Stromal Cells via Hypoxia-Inducible Factor 1alpha Upregulation-Mediated beta-Catenin Activation in Endometriosis. Reprod Sci 2016; 23: 531-541.
31. Xu TX, Zhao SZ, Dong M, et al. Hypoxia responsive miR-210 promotes cell survival and autophagy of endometriotic cells in hypoxia. Eur Rev Med Pharmacol Sci 2016; 20: 399-406.
32. Wu MH, Chuang PC, Chen HM, et al. Increased leptin expression in endometriosis cells is associated with endometrial stromal cell proliferation and leptin gene up-regulation. Mol Hum Reprod 2002; 8: 456-464.
33. Wu MH, Chen KF, Lin SC, et al. Aberrant expression of leptin in human endometriotic stromal cells is induced by elevated levels of hypoxia inducible factor-1alpha. Am J Pathol 2007; 170: 590-598.
34. Lu Z, Zhang W, Jiang S, et al. Effect of oxygen tensions on the proliferation and angiogenesis of endometriosis heterograft in severe combined immunodeficiency mice. Fertil Steril 2014; 101: 568-576.
35. Hsiao KY, Wu MH, Chang N, et al. Coordination of AUF1 and miR-148a to destabilize DNA methyltransferase 1 mRNA under hypoxia in endometriosis. Mol Hum Reprod 2015.
36. Nasu K, Kawano Y, Tsukamoto Y, et al. Aberrant DNA methylation status of endometriosis: epigenetics as the pathogenesis, biomarker and therapeutic target. J Obstet Gynaecol Res 2011; 37: 683-695.
37. Koukoura O, Sifakis S, Spandidos DA. DNA methylation in endometriosis (Review). Mol Med Rep 2016; 13: 2939-2948.
38. Critchley HO, Osei J, Henderson TA, et al. Hypoxia-inducible factor-1alpha expression in human endometrium and its regulation by prostaglandin E-series prostanoid receptor 2 (EP2). Endocrinology 2006; 147: 744-753.
39. Gazvani R, Templeton A. Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis. Reproduction (Cambridge, England) 2002; 123: 217-226.
40. Zhang L, Xiong W, Li N, et al. Estrogen stabilizes hypoxia-inducible factor 1α through G protein-coupled estrogen receptor 1 in eutopic endometrium of endometriosis. Fertil Steril 2017; 107: 439-447.
41. Nikami H, Nedergaard J, Fredriksson JM. Norepinephrine but not hypoxia stimulates HIF-1alpha gene expression in brown adipocytes. Biochem Biophys Res Commun 2005; 337: 121-126.
42. Wu MH, Hsiao KY, Tsai SJ. Endometriosis and possible inflammation markers. Gynecology and Minimally Invasive Therapy 2015; 4: 61-67.
43. Capobianco A, Rovere-Querini P. Endometriosis, a disease of the macrophage. Front Immunol 2013; 4: 9.
44. Yu L, Wu WK, Li ZJ, et al. Prostaglandin E(2) promotes cell proliferation via protein kinase C/extracellular signal regulated kinase pathway-dependent induction of c-Myc expression in human esophageal squamous cell carcinoma cells. Int J Cancer 2009; 125: 2540-2546.
45. Krause P, Bruckner M, Uermosi C, et al. Prostaglandin E(2) enhances T-cell proliferation by inducing the costimulatory molecules OX40L, CD70, and 4-1BBL on dendritic cells. Blood 2009; 113: 2451-2460.
46. Finetti F, Solito R, Morbidelli L, et al. Prostaglandin E2 regulates angiogenesis via activation of fibroblast growth factor receptor-1. J Biol Chem 2008; 283: 2139-2146.
47. Syeda MM, Jing X, Mirza RH, et al. Prostaglandin transporter modulates wound healing in diabetes by regulating prostaglandin-induced angiogenesis. Am J Pathol 2012; 181: 334-346.
48. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol 2011; 31: 986-1000.
49. Aoki T, Narumiya S. Prostaglandins and chronic inflammation. Trends Pharmacol Sci 2012; 33: 304-311.
50. Wu MH, Lin SC, Hsiao KY, et al. Hypoxia-inhibited dual-specificity phosphatase-2 expression in endometriotic cells regulates cyclooxygenase-2 expression. J Pathol 2011; 225: 390-400.
51. Lee JJ, Natsuizaka M, Ohashi S, et al. Hypoxia activates the cyclooxygenase-2-prostaglandin E synthase axis. Carcinogenesis 2010; 31: 427-434.
52. Banu SK, Lee J, Speights VO, Jr., et al. Cyclooxygenase-2 regulates survival, migration, and invasion of human endometriotic cells through multiple mechanisms. Endocrinology 2008; 149: 1180-1189.
53. Attar E, Tokunaga H, Imir G, et al. Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis. J Clin Endocrinol Metab 2009; 94: 623-631.
54. Monsivais D, Dyson MT, Yin P, et al. ERbeta- and prostaglandin E2-regulated pathways integrate cell proliferation via Ras-like and estrogen-regulated growth inhibitor in endometriosis. Mol Endocrinol 2014; 28: 1304-1315.
55. Hsiao KY, Chang N, Tsai JL, et al. Hypoxia-inhibited DUSP2 expression promotes IL-6/STAT3 signaling in endometriosis. Am J Reprod Immunol 2017.
56. Hotchkiss RS, Strasser A, McDunn JE, et al. Cell death. N Engl J Med 2009; 361: 1570-1583.
57. Labbe K, Saleh M. Cell death in the host response to infection. Cell Death Differ 2008; 15: 1339-1349.
58. Duprez L, Wirawan E, Vanden Berghe T, et al. Major cell death pathways at a glance. Microbes and infection / Institut Pasteur 2009; 11: 1050-1062.
59. Portt L, Norman G, Clapp C, et al. Anti-apoptosis and cell survival: A review. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 2011; 1813: 238-259.
60. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol 2007; 35: 495-516.
61. Meresman GF, Vighi S, Buquet RA, et al. Apoptosis and expression of Bcl-2 and Bax in eutopic endometrium from women with endometriosis. Fertil Steril 2000; 74: 760-766.
62. Harada T, Kaponis A, Iwabe T, et al. Apoptosis in human endometrium and endometriosis. Hum Reprod Update 2004; 10: 29-38.
63. Jones RK, Searle RF, Bulmer JN. Apoptosis and bcl-2 expression in normal human endometrium, endometriosis and adenomyosis. Hum Reprod 1998; 13: 3496-3502.
64. Watanabe H, Kanzaki H, Narukawa S, et al. Bcl-2 and Fas expression in eutopic and ectopic human endometrium during the menstrual cycle in relation to endometrial cell apoptosis. Am J Obstet Gynecol 1997; 176: 360-368.
65. Taniguchi F, Kaponis A, Izawa M, et al. Apoptosis and endometriosis. Frontiers in bioscience (Elite edition) 2011; 3: 648-662.
66. Bilotas M, Meresman G, Buquet R, et al. Effect of vascular endothelial growth factor and interleukin-1beta on apoptosis in endometrial cell cultures from patients with endometriosis and controls. J Reprod Immunol 2010; 84: 193-198.
67. Abe W, Nasu K, Nakada C, et al. miR-196b targets c-myc and Bcl-2 expression, inhibits proliferation and induces apoptosis in endometriotic stromal cells. Hum Reprod 2013; 28: 750-761.
68. Pellegrini C, Gori I, Achtari C, et al. The expression of estrogen receptors as well as GREB1, c-MYC, and cyclin D1, estrogen-regulated genes implicated in proliferation, is increased in peritoneal endometriosis. Fertil Steril 2012; 98: 1200-1208.
69. Wechsler DS, Shelly CA, Dang CV. Genomic organization of human MXI1, a putative tumor suppressor gene. Genomics 1996; 32: 466-470.
70. Lofstedt T, Fredlund E, Noguera R, et al. HIF-1alpha induces MXI1 by alternate promoter usage in human neuroblastoma cells. Exp Cell Res 2009; 315: 1924-1936.
71. Grandori C, Cowley SM, James LP, et al. The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu Rev Cell Dev Biol 2000; 16: 653-699.
72. Dugast-Darzacq C, Grange T, Schreiber-Agus NB. Differential effects of Mxi1-SRalpha and Mxi1-SRbeta in Myc antagonism. The FEBS journal 2007; 274: 4643-4653.
73. Engstrom LD, Youkilis AS, Gorelick JL, et al. Mxi1-0, an alternatively transcribed Mxi1 isoform, is overexpressed in glioblastomas. Neoplasia 2004; 6: 660-673.
74. Harper SE, Qiu Y, Sharp PA. Sin3 corepressor function in Myc-induced transcription and transformation. Proc Natl Acad Sci U S A 1996; 93: 8536-8540.
75. Dugast-Darzacq C, Pirity M, Blanck JK, et al. Mxi1-SRalpha: a novel Mxi1 isoform with enhanced transcriptional repression potential. Oncogene 2004; 23: 8887-8899.
76. Schreiber-Agus N, Chin L, Chen K, et al. An amino-terminal domain of Mxi1 mediates anti-Myc oncogenic activity and interacts with a homolog of the yeast transcriptional repressor SIN3. Cell 1995; 80: 777-786.
77. Zervos AS, Gyuris J, Brent R. Mxi1, a protein that specifically interacts with Max to bind Myc-Max recognition sites. Cell 1993; 72: 223-232.
78. Hurlin PJ, Huang J. The MAX-interacting transcription factor network. Semin Cancer Biol 2006; 16: 265-274.
79. Schreiber-Agus N, Meng Y, Hoang T, et al. Role of Mxi1 in ageing organ systems and the regulation of normal and neoplastic growth. Nature 1998; 393: 483-487.
80. Corn PG, Ricci MS, Scata KA, et al. Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis. Cancer Biol Ther 2005; 4: 1285-1294.
81. Armstrong MB, Mody RJ, Ellis DC, et al. N-Myc differentially regulates expression of MXI1 isoforms in neuroblastoma. Neoplasia 2013; 15: 1363-1370.
82. Erichsen DA, Armstrong MB, Wechsler DS. Mxi1 and mxi1-0 antagonize N-myc function and independently mediate apoptosis in neuroblastoma. Transl Oncol 2015; 8: 65-74.
83. Cascon A, Robledo M. MAX and MYC: a heritable breakup. Cancer Res 2012; 72: 3119-3124.
84. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997; 67: 817-821.
85. Allen J, Winterford C, Axelsen RA, et al. Effects of hypoxia on morphological and biochemical characteristics of renal epithelial cell and tubule cultures. Ren Fail 1992; 14: 453-460.
86. Malhotra R, Lin Z, Vincenz C, et al. Hypoxia induces apoptosis via two independent pathways in Jurkat cells: differential regulation by glucose. Am J Physiol Cell Physiol 2001; 281: C1596-1603.
87. Lin SC, Chien CW, Lee JC, et al. Suppression of dual-specificity phosphatase-2 by hypoxia increases chemoresistance and malignancy in human cancer cells. J Clin Invest 2011; 121: 1905-1916.
88. Sermeus A, Genin M, Maincent A, et al. Hypoxia-induced modulation of apoptosis and BCL-2 family proteins in different cancer cell types. PLoS One 2012; 7: e47519.
89. Xu W, Zhou W, Cheng M, et al. Hypoxia activates Wnt/β-catenin signaling by regulating the expression of BCL9 in human hepatocellular carcinoma. 2017; 7: 40446.
90. Zhang Q, Bai X, Chen W, et al. Wnt/beta-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1alpha signaling. Carcinogenesis 2013; 34: 962-973.
91. Sheng L, Mao X, Yu Q, et al. Effect of the PI3K/AKT signaling pathway on hypoxia-induced proliferation and differentiation of bone marrow-derived mesenchymal stem cells. Exp Ther Med 2017; 13: 55-62.
92. Song Y, Zheng S, Wang J, et al. Hypoxia-induced PLOD2 promotes proliferation, migration and invasion via PI3K/Akt signaling in glioma. Oncotarget 2017.
93. Ma B, Chen Y, Chen L, et al. Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase. Nat Cell Biol 2015; 17: 95-103.
94. Bae JS, Kim SM, Lee H. The Hippo signaling pathway provides novel anti-cancer drug targets. Oncotarget 2017; 8: 16084-16098.
95. Wang C, Jin A, Huang W, et al. Up-regulation of Bcl-2 by CD147 Through ERK Activation Results in Abnormal Cell Survival in Human Endometriosis. J Clin Endocrinol Metab 2015; 100: E955-963.
96. Okamoto M, Nasu K, Abe W, et al. Enhanced miR-210 expression promotes the pathogenesis of endometriosis through activation of signal transducer and activator of transcription 3. Hum Reprod 2015; 30: 632-641.
97. Lin SC, Lee HC, Hou PC, et al. Targeting hypoxia-mediated YAP1 nuclear translocation ameliorates pathogenesis of endometriosis without compromising maternal fertility. J Pathol 2017.
98. Chen H, Song Y, Yang S, et al. YAP mediates human decidualization of the uterine endometrial stromal cells. Placenta 2017; 53: 30-35.
99. Gogacz M, Bogusiewicz M, Putowski L, et al. [Expression of tumor necrosis factor-alpha (TNF-alpha) on peritoneal fluid mononuclear cells in women with endometriosis]. Ginekol Pol 2008; 79: 31-35.
100. Iwabe T, Harada T, Tsudo T, et al. Tumor necrosis factor-alpha promotes proliferation of endometriotic stromal cells by inducing interleukin-8 gene and protein expression. J Clin Endocrinol Metab 2000; 85: 824-829.
101. Tian X, Xu L, Wang P. MiR-191 inhibits TNF-alpha induced apoptosis of ovarian endometriosis and endometrioid carcinoma cells by targeting DAPK1. Int J Clin Exp Pathol 2015; 8: 4933-4942.
102. Zervos AS, Gyuris J, Brent R. Mxi1, a protein that specifically interacts with Max to bind Myc-Max recognition sites. Cell 1994; 79: following 388.
103. Ko JY, Yoo KH, Lee HW, et al. Mxi1 regulates cell proliferation through insulin-like growth factor binding protein-3. Biochem Biophys Res Commun 2011; 415: 36-41.
104. Zhou J, Wang W, Gao Z, et al. MicroRNA-155 Promotes Glioma Cell Proliferation via the Regulation of MXI1. PLoS One 2013; 8: e83055.
105. Taj MM, Tawil RJ, Engstrom LD, et al. Mxi1, a Myc antagonist, suppresses proliferation of DU145 human prostate cells. Prostate 2001; 47: 194-204.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2020-08-01起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2020-08-01起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw