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博碩士論文 etd-0325117-160833 詳細資訊
Title page for etd-0325117-160833
論文名稱
Title
miRNAs 及自噬在肝癌中的調控及治療上之探討
The regulation and treatment of miRNAs and autophagy in hepatocellular carcinoma
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
93
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2017-04-21
繳交日期
Date of Submission
2017-04-25
關鍵字
Keywords
肝細胞癌、miRNAs、自噬、miRNAs治療、自噬治療
autophagy therapy, miRNAs therapy, autophagy, Hepatocellular carcinoma, miRNAs
統計
Statistics
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The thesis/dissertation has been browsed 5727 times, has been downloaded 777 times.
中文摘要
肝細胞癌 (HCC) 是人類最常見的惡性腫瘤,它是全世界排名第五名的惡性腫瘤,也是全球癌症相關死亡的第三大常見原因。最近的研究顯示,miRNAs會涉及到許多癌症,包括肝細胞癌。MicroRNAs (miRNAs) 為一個大約有22個核苷酸小的非編碼RNAs,它涉及了許多生理功能像是發育、細胞增殖、細胞凋亡以及自噬。我們利用NCBI pubmed搜尋,在肝細胞癌中涉及miRNAs和自噬的影響的相關文獻,並且利用miRmine網站搜尋在肝細胞癌中各種的miRNAs,接著將其彙整,以便找出肝細胞癌中的自噬以及miRNAs的關聯性。雖然有少數文獻指出,miRNAs和自噬以及肝細胞癌中的影響,但三者的關係仍然有待確定。我們也探討miRNAs對於自噬的調控,以及miRNAs在自噬中的治療作用,希望有朝一日能應用在癌症中,並降低復發率。
Abstract
Hepatocellular carcinoma (HCC) is the most common type and malignant tumors in human worldwide, and it ranks as the fifth most frequent cancer and the third leading cause of cancer mortality worldwide. Recent study reported that miRNAs are involved in many cancers, including hepatocellular carcinoma. MicroRNAs (miRNAs) are a non-coding RNAs of approximately 22 nucleotides that involve several biological processes such as development, cell proliferation, apoptosis, and autophagy. We use NCBI pubmed to search for related literature on the effects of miRNAs and autophagy in hepatocellular carcinoma. In addition, we used miRmine website to search for differentiaed miRNAs in HCC. Then, we aggregated to identify the association of autophagy and miRNAs in hepatocellular carcinoma. Although there are a few literatures that show the effects of miRNAs and autophagy in HCC. However, the relationship between miRNAs and autophagy in HCC remains to be determined. At last, we also explored the regulation of miRNAs for autophagy and the therapeutic effect of miRNAs in autophagy, hoping to be used in cancer one day and reduce the recurrence rate.
目次 Table of Contents
論文審定書 i
論文公開授權書 ii
中文摘要 iii
Abstract iv
英文縮寫表 v
圖次 xiii
表次 xiv
壹、 緒論 1
貳、 肝細胞癌 4
貳.1. 肝臟的結構與生理功能 4
貳.2. 肝癌的發生及症狀 5
貳.3. 肝癌的種類 5
貳.4. 肝癌的危險因子 7
貳.5. 肝癌的臨床分期 8
貳.6. 肝癌的治療方式 10
參、 MicroRNAs (miRNAs) 12
參.1. miRNAs的起源 12
參.2. miRNAs的生成 13
肆、 自噬 (autophagy) 15
肆.1. 自噬 15
肆.2. 自噬的生成過程 16
伍、 材料與方法 17
陸、 實驗流程 18
柒、 miRNAs在肝癌中的角色 19
捌、 miRNAs與自噬 (autophagy) 的關係 22
捌.1. miRNAs調控自噬機制 22
捌.2. miRNAs調控自噬造成致癌性 23
捌.3. miRNAs調控自噬造成抑癌作用 24
玖、 自噬的潛在治療作用 26
玖.1. miRNAs在自噬中潛在的治療作用 26
玖.2. 在HCC中,粒線體分裂會誘導自噬活化的治療潛力 28
壹拾、 結果 29
壹拾.1. 在肝癌中,幾個miRNAs已被證實會影響自噬 29
壹拾壹、 結論 49
參考文獻 50
附錄 73
參考文獻 References
1. World Health Organization. February 2017.
2. 行政院衛生署, 104年死因統計. 2016.
3. Jin, F., et al., MiR-26 enhances chemosensitivity and promotes apoptosis of hepatocellular carcinoma cells through inhibiting autophagy. Cell Death Dis, 2017. 8(1): p. e2540.
4. Gong, X.L. and S.K. Qin, Progress in systemic therapy of advanced hepatocellular carcinoma. World J Gastroenterol, 2016. 22(29): p. 6582-6594.
5. Bartel, D.P., MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. Cell, 2004. 116(2): p. 281-297.
6. Inui, M., G. Martello, and S. Piccolo, MicroRNA control of signal transduction. Nat Rev Mol Cell Biol, 2010. 11(4): p. 252-263.
7. Tang, J., A. Ahmad, and F.H. Sarkar, The Role of MicroRNAs in Breast Cancer Migration, Invasion and Metastasis. International Journal of Molecular Sciences, 2012. 13(10): p. 13414-13437.
8. Casalini, P. and M.V. Iorio, MicroRNAs and future therapeutic applications in cancer. J BUON, 2009. 14 Suppl 1: p. S17-22.
9. Croce, C.M., Causes and consequences of microRNA dysregulation in cancer. Nature reviews. Genetics, 2009. 10(10): p. 704-714.
10. Ma, L., J. Teruya-Feldstein, and R.A. Weinberg, Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature, 2007. 449(7163): p. 682-688.
11. Valastyan, S. and R.A. Weinberg, MicroRNAs: Crucial multi-tasking components in the complex circuitry of tumor metastasis. Cell Cycle, 2009. 8(21): p. 3506-3512.
12. Ahmad, A., et al., Phosphoglucose Isomerase/Autocrine Motility Factor mediates epithelial-mesenchymal transition regulated by miR-200 in breast cancer cells. Cancer research, 2011. 71(9): p. 3400-3409.
13. White, E., et al., Role of autophagy in suppression of inflammation and cancer. Curr Opin Cell Biol, 2010. 22(2): p. 212-217.
14. Rubinsztein, D.C., P. Codogno, and B. Levine, Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov, 2012. 11(9): p. 709-730.
15. Rouschop, K.M.A., et al., Autophagy is required during cycling hypoxia to lower production of reactive oxygen species. Radiotherapy and Oncology, 2009. 92(3): p. 411-416.
16. Mazure, N.M. and J. Pouysségur, Hypoxia-induced autophagy: cell death or cell survival? Current Opinion in Cell Biology, 2010. 22(2): p. 177-180.
17. Degenhardt, K., et al., Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell, 2006. 10(1): p. 51-64.
18. Mathew, R., V. Karantza-Wadsworth, and E. White, Role of autophagy in cancer. Nature reviews. Cancer, 2007. 7(12): p. 961-967.
19. Rautou, P.E., et al., Autophagy in liver diseases. J Hepatol, 2010. 53(6): p. 1123-1134.
20. Zheng, Y.S., et al., MiR-100 regulates cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia. Oncogene, 2012. 31(1): p. 80-92.
21. Petrelli, A., et al., Sequential analysis of multistage hepatocarcinogenesis reveals that miR-100 and PLK1 dysregulation is an early event maintained along tumor progression. Oncogene, 2012. 31(42): p. 4517-4526.
22. Gebeshuber, C.A. and J. Martinez, miR-100 suppresses IGF2 and inhibits breast tumorigenesis by interfering with proliferation and survival signaling. Oncogene, 2013. 32(27): p. 3306-3310.
23. Xu, C., et al., miRNA-100 Inhibits Human Bladder Urothelial Carcinogenesis by Directly Targeting mTOR. Molecular Cancer Therapeutics, 2013. 12(2): p. 207.
24. Zhai, H., A. Fesler, and J. Ju, MicroRNA: A third dimension in autophagy. Cell Cycle, 2013. 12(2): p. 246-250.
25. Zhu, H., et al., Regulation of autophagy by a beclin 1-targeted microRNA, miR-30a, in cancer cells. Autophagy, 2009. 5(6): p. 816-823.
26. Frankel, L.B., et al., microRNA-101 is a potent inhibitor of autophagy. E M B O Journal, 2011. 30: p. 4628-4641.
27. Zhai, H., et al., Inhibition of autophagy and tumor growth in colon cancer by miR-502. Oncogene, 2013. 32(12): p. 1570-1579.
28. Chang, Y., et al., miR-375 inhibits autophagy and reduces viability of hepatocellular carcinoma cells under hypoxic conditions. Gastroenterology, 2012. 143(1): p. 177-187 e8.
29. Ge, Y.-Y., et al., MicroRNA-100 promotes the autophagy of hepatocellular carcinoma cells by inhibiting the expression of mTOR and IGF-1R. Oncotarget, 2014. 5(15): p. 6218-6228.
30. Xu, L., et al., MicroRNA-101 inhibits human hepatocellular carcinoma progression through EZH2 downregulation and increased cytostatic drug sensitivity. J Hepatol, 2014. 60(3): p. 590-598.
31. Xu, N., et al., Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell. Biochem Biophys Res Commun, 2012. 423(4): p. 826-831.
32. Lan, S.H., et al., Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of microRNA-224. Hepatology, 2014. 59(2): p. 505-517.
33. Parkin, D.M., et al., Global cancer statistics, 2002. CA Cancer J Clin, 2005. 55.
34. Fattovich, G., et al., Hepatocellular carcinoma in cirrhosis: Incidence and risk factors. Gastroenterology, 2004. 127(5): p. S35-S50.
35. Forner, A., et al., Current strategy for staging and treatment: the BCLC update and future prospects. . Semin Liver Dis, 2010. 30: p. 61-74.
36. Marrero, J.A., et al., Prognosis of hepatocellular carcinoma: Comparison of 7 staging systems in an American cohort. Hepatology, 2005. 41(4): p. 707-715.
37. Cillo, U., et al., Prospective validation of the Barcelona Clinic Liver Cancer staging system. Journal of Hepatology, 2008. 44(4): p. 723-731.
38. Bruix, J., M. Sala, and J.M. Llovet, Chemoembolization for hepatocellular carcinoma. Gastroenterology, 2004. 127(5): p. S179-S188.
39. Lee, R.C., R.L. Feinbaum, and V. Ambros, The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell, 1993. 75(5): p. 843-854.
40. Wightman, B., I. Ha, and G. Ruvkun, Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell, 1993. 75(5): p. 855-862.
41. Brennecke, J., et al., bantam Encodes a Developmentally Regulated microRNA that Controls Cell Proliferation and Regulates the Proapoptotic Gene hid in Drosophila. Cell, 2003. 113(1): p. 25-36.
42. Xu, P., et al., The Drosophila MicroRNA Mir-14 Suppresses Cell Death and Is Required for Normal Fat Metabolism. Current Biology, 2003. 13(9): p. 790-795.
43. Johnston, R.J. and O. Hobert, A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans. Nature, 2003. 426(6968): p. 845-849.
44. Chen, C.-Z., et al., MicroRNAs Modulate Hematopoietic Lineage Differentiation. Science, 2004. 303(5654): p. 83-86.
45. Aukerman, M.J. and H. Sakai, Regulation of Flowering Time and Floral Organ Identity by a MicroRNA and Its APETALA2-Like Target Genes. The Plant Cell, 2003. 15(11): p. 2730-2741.
46. Emery, J.F., et al., Radial Patterning of Arabidopsis Shoots by Class III HD-ZIP and KANADI Genes. Current Biology, 2003. 13(20): p. 1768-1774.
47. Palatnik, J.F., et al., Control of leaf morphogenesis by microRNAs. Nature, 2003. 425(6955): p. 257-263.
48. Reinhart, B.J., et al., The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature, 2000. 403(6772): p. 901-906.
49. Slack, F.J., et al., The lin-41 RBCC Gene Acts in the C. elegans Heterochronic Pathway between the let-7 Regulatory RNA and the LIN-29 Transcription Factor. Molecular Cell, 2000. 5(4): p. 659-669.
50. Pasquinelli, A.E., et al., Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature, 2000. 408(6808): p. 86-89.
51. Lau, N.C., et al., An Abundant Class of Tiny RNAs with Probable Regulatory Roles in Caenorhabditis elegans. Science, 2001. 294(5543): p. 858-862.
52. Lagos-Quintana, M., et al., Identification of Novel Genes Coding for Small Expressed RNAs. Science, 2001. 294(5543): p. 853-858.
53. Lagos-Quintana, M., et al., Identification of Tissue-Specific MicroRNAs from Mouse. Current Biology, 2002. 12(9): p. 735-739.
54. Lee, Y., et al., MicroRNA maturation: stepwise processing and subcellular localization. The EMBO Journal, 2002. 21(17): p. 4663-4670.
55. Aravin, A.A., et al., The Small RNA Profile during Drosophila melanogaster Development. Developmental Cell, 2003. 5(2): p. 337-350.
56. Ohler, U.W.E., et al., Patterns of flanking sequence conservation and a characteristic upstream motif for microRNA gene identification. RNA, 2004. 10(9): p. 1309-1322.
57. Mizushima, N., et al., Autophagy fights disease through cellular self-digestion. Nature, 2008. 451(7182): p. 1069-1075.
58. Mehrpour, M., et al., Autophagy in health and disease. 1. Regulation and significance of autophagy: an overview. American Journal of Physiology - Cell Physiology, 2010. 298(4): p. C776-C785.
59. Hailey, D.W., et al., Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell, 2010. 141(4): p. 656-667.
60. Yao, D., et al., Deconvoluting the complexity of microRNAs in autophagy to improve potential cancer therapy. Cell Prolif, 2016. 49(5): p. 541-553.
61. Chen, K.-j., et al., Reexpression of Let-7g MicroRNA Inhibits the Proliferation and Migration via K-Ras/HMGA2/Snail Axis in Hepatocellular Carcinoma. BioMed Research International, 2014. 2014: p. 742417.
62. Nassirpour, R., P.P. Mehta, and M.-J. Yin, miR-122 Regulates Tumorigenesis in Hepatocellular Carcinoma by Targeting AKT3. PLoS ONE, 2013. 8(11): p. e79655.
63. Wang, S.-C., et al., MicroRNA-122 Triggers Mesenchymal-Epithelial Transition and Suppresses Hepatocellular Carcinoma Cell Motility and Invasion by Targeting RhoA. PLOS ONE, 2014. 9(7): p. e101330.
64. Jin, J., et al., MicroRNA‑122 regulation of the morphology and cytoarchitecture of hepatoma carcinoma cells. Molecular Medicine Reports, 2014. 9: p. 1376-1380.
65. Xing, T.J., et al., Methylation regulation of liver-specific microRNA-122 expression and its effects on the proliferation and apoptosis of hepatocellular carcinoma cells. Genet Mol Res, 2013. 12: p. 3588-3597.
66. Zhang, J., et al., Propofol inhibits the adhesion of hepatocellular carcinoma cells by upregulating microRNA-199a and downregulating MMP-9 expression. Hepatobiliary Pancreat Dis Int, 2013. 12: p. 305-309.
67. Song, J., et al., MiR-199a Regulates Cell Proliferation and Survival by Targeting FZD7. PLoS ONE, 2014. 9(10): p. e110074.
68. Henry, J.C., et al., miR-199a-3p targets CD44 and reduces proliferation of CD44 positive hepatocellular carcinoma cell lines. Biochemical and biophysical research communications, 2010. 403(1): p. 120-125.
69. Fornari, F., et al., MiR-199a-3p Regulates mTOR and c-Met to Influence the Doxorubicin Sensitivity of Human Hepatocarcinoma Cells. Cancer Research, 2010. 70(12): p. 5184-5193.
70. Shen, Q., et al., Role of microRNA-199a-5p and discoidin domain receptor 1 in human hepatocellular carcinoma invasion. Molecular Cancer, 2010. 9: p. 227-227.
71. Lee, J.M., et al., Increase of miR-199a-5p by protoporphyrin IX, a photocatalyzer, directly inhibits E2F3, sensitizing mesenchymal tumor cells to anti-cancer agents. Oncotarget, 2015. 6(6): p. 3918-3931.
72. Bao, L., et al., MicroRNA-21 suppresses PTEN and hSulf-1 expression and promotes hepatocellular carcinoma progression through AKT/ERK pathways. Cancer Letters, 2013. 337(2): p. 226-236.
73. Hu, S., et al., MicroRNA-21 promotes cell proliferation in human hepatocellular carcinoma partly by targeting HEPN1. Tumor Biology, 2015. 36(7): p. 5467-5472.
74. Xu, G., et al., MicroRNA-21 promotes hepatocellular carcinoma HepG2 cell proliferation through repression of mitogen-activated protein kinase-kinase 3. BMC Cancer. , 2013. 13: p. 469.
75. Yao, Q., et al., MicroRNA-21 promotes cell proliferation and down-regulates the expression of programmed cell death 4 (PDCD4) in HeLa cervical carcinoma cells. Biochem Biophys Res Commun, 2009. 388.
76. Gramantieri, L., et al., MicroRNA-221 Targets Bmf in Hepatocellular Carcinoma and Correlates with Tumor Multifocality. Clinical cancer research : an official journal of the American Association for Cancer Research, 2009. 15(16): p. 5073-5081.
77. Ma, D., et al., miR-224 functions as an onco-miRNA in hepatocellular carcinoma cells by activating AKT signaling. Oncology Letters, 2012. 4(3): p. 483-488.
78. Li, Q., et al., miR-224 promotion of cell migration and invasion by targeting Homeobox D 10 gene in human hepatocellular carcinoma. Journal of Gastroenterology and Hepatology, 2014. 29(4): p. 835-842.
79. Tschan, M.P., et al., The Autophagy Gene ULK1 Plays a Role In AML Differentiation and Is Negatively Regulated by the Oncogenic MicroRNA 106a. Blood, 2010. 116(21): p. 503-503.
80. Wu, H., et al., MiR-20a and miR-106b negatively regulate autophagy induced by leucine deprivation via suppression of ULK1 expression in C2C12 myoblasts. Cellular Signalling, 2012. 24(11): p. 2179-2186.
81. Huang, Y., A.Y. Chuang, and E.A. Ratovitski, Phospho-ΔNp63α/miR-885-3p axis in tumor cell life and cell death upon cisplatin exposure. Cell Cycle, 2011. 10(22): p. 3938-3947.
82. John Clotaire, D.Z., et al., miR-26b inhibits autophagy by targeting ULK2 in prostate cancer cells. Biochemical and Biophysical Research Communications, 2016. 472(1): p. 194-200.
83. Li, S., et al., MiR-20a and miR-20b negatively regulate autophagy by targeting RB1CC1/FIP200 in breast cancer cells. Life Sciences, 2016. 147: p. 143-152.
84. Wan, G., et al., Hypoxia-induced MIR155 is a potent autophagy inducer by targeting multiple players in the MTOR pathway. Autophagy, 2014. 10(1): p. 70-79.
85. Xu, Y., et al., miR-101 inhibits autophagy and enhances cisplatin-induced apoptosis in hepatocellular carcinoma cells. Oncology Reports, 2013. 29: p. 2019-2024.
86. Meenhuis, A., et al., MiR-17/20/93/106 promote hematopoietic cell expansion by targeting sequestosome 1–regulated pathways in mice. Blood, 2011. 118(4): p. 916-925.
87. Yang, X., et al., mir-30d regulates multiple genes in the autophagy pathway and impairs autophagy process in human cancer cells. Biochemical and biophysical research communications, 2013. 431(3): p. 617-622.
88. Korkmaz, G., et al., miR-376b controls starvation and mTOR inhibition-related autophagy by targeting ATG4C and BECN1. Autophagy, 2012. 8(2): p. 165-176.
89. Tan, S., et al., miR-409-3p sensitizes colon cancer cells to oxaliplatin by inhibiting Beclin-1-mediated autophagy. . International Journal of Molecular Medicine, 2016. 37: p. 1030-1038.
90. Chatterjee, A., D. Chattopadhyay, and G. Chakrabarti, miR-17-5p Downregulation Contributes to Paclitaxel Resistance of Lung Cancer Cells through Altering Beclin1 Expression. PLOS ONE, 2014. 9(4): p. e95716.
91. Zhang, X., et al., MicroRNA-216a enhances the radiosensitivity of pancreatic cancer cells by inhibiting beclin-1-mediated autophagy. Oncology Reports, 2015. 34: p. 1557-1564.
92. Chen, K. and W. Shi, Autophagy regulates resistance of non-small cell lung cancer cells to paclitaxel. Tumor Biology, 2016. 37(8): p. 10539-10544.
93. He, C. and B. Levine, The Beclin 1 interactome. Current opinion in cell biology, 2010. 22(2): p. 140-149.
94. He, J., et al., Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy. Autophagy, 2015. 11(2): p. 373-384.
95. Huang, Y., R. Guerrero-Preston, and E.A. Ratovitski, Phospho-ΔNp63α-dependent regulation of autophagic signaling through transcription and micro-RNA modulation. Cell Cycle, 2012. 11(6): p. 1247-1259.
96. Huangfu, L., et al., miR-183 regulates autophagy and apoptosis in colorectal cancer through targeting of UVRAG. Oncotarget, 2016. 7(4): p. 4735-4745.
97. Comincini, S., et al., microRNA-17 regulates the expression of ATG7 and modulates the autophagy process, improving the sensitivity to temozolomide and low-dose ionizing radiation treatments in human glioblastoma cells. Cancer Biology & Therapy, 2013. 14(7): p. 574-586.
98. Jian, X., et al., MiR-204 regulate cardiomyocyte autophagy induced by hypoxia-reoxygenation through LC3-II. Int J Cardiol, 2011. 148.
99. Mikhaylova, O., et al., VHL-regulated miR-204 Suppresses Tumor Growth through Inhibition of LC3B-mediated Autophagy in Renal Clear Cell Carcinoma. Cancer Cell, 2012. 21(4): p. 532-546.
100. Christoffersen, N.R., et al., p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC. Cell Death Differ, 2009. 17(2): p. 236-245.
101. Pennati, M., et al., miR-205 impairs the autophagic flux and enhances cisplatin cytotoxicity in castration-resistant prostate cancer cells. . Biochem Pharmacol., 2014. 87: p. 579–597.
102. Wang, Z., et al., MicroRNA-25 regulates chemoresistance-associated autophagy in breast cancer cells, a process modulated by the natural autophagy inducer isoliquiritigenin. Oncotarget, 2014. 5(16): p. 7013-7026.
103. Chen, Y., R. Liersch, and M. Detmar, The miR-290-295 cluster suppresses autophagic cell death of melanoma cells. Scientific Reports, 2012. 2: p. 808.
104. Gwak, H.-S., et al., Silencing of MicroRNA-21 Confers Radio-Sensitivity through Inhibition of the PI3K/AKT Pathway and Enhancing Autophagy in Malignant Glioma Cell Lines. PLOS ONE, 2012. 7(10): p. e47449.
105. Yu, X., et al., Silencing of MicroRNA-21 confers the sensitivity to tamoxifen and fulvestrant by enhancing autophagic cell death through inhibition of the PI3K-AKT-mTOR pathway in breast cancer cells. Biomedicine & Pharmacotherapy, 2016. 77: p. 37-44.
106. Chatterjee, A., D. Chattopadhyay, and G. Chakrabarti, miR-16 targets Bcl-2 in paclitaxel-resistant lung cancer cells and overexpression of miR-16 along with miR-17 causes unprecedented sensitivity by simultaneously modulating autophagy and apoptosis. Cellular Signalling, 2015. 27(2): p. 189-203.
107. Abraham, D., et al., MicroRNA Profiling of Sporadic and Hereditary Medullary Thyroid Cancer Identifies Predictors of Nodal Metastasis, Prognosis, and Potential Therapeutic Targets. Clinical Cancer Research, 2011. 17(14): p. 4772-4781.
108. Sümbül, A.T., et al., miR-204-5p expression in colorectal cancer: an autophagy-associated gene. Tumor Biology, 2014. 35(12): p. 12713-12719.
109. Pavlides, S., et al., The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism. Cell Cycle, 2010. 9(17): p. 3485-3505.
110. Tekirdag, K.A., et al., MIR181A regulates starvation- and rapamycin-induced autophagy through targeting of ATG5. Autophagy, 2013. 9(3): p. 374-385.
111. Zhao, J., et al., MiR-181a suppresses autophagy and sensitizes gastric cancer cells to cisplatin. Gene, 2016. 576(2 Pt 2): p. 828-833.
112. Guo, X., et al., MiR224-3p inhibits hypoxia-induced autophagy by targeting autophagy-related genes in human glioblastoma cells. Oncotarget, 2015. 6(39): p. 41620-41637.
113. Wang, P., et al., MicroRNA 23b Regulates Autophagy Associated With Radioresistance of Pancreatic Cancer Cells. Gastroenterology, 2013. 145(5): p. 1133-1143.e12.
114. An, Y., et al., miR-23b-3p regulates the chemoresistance of gastric cancer cells by targeting ATG12 and HMGB2. Cell Death Dis, 2015. 6: p. e1766.
115. Zhai, H., et al., Inhibition of colorectal cancer stem cell survival and invasive potential by hsa-miR-140-5p mediated suppression of Smad2 and autophagy. Oncotarget, 2015. 6(23): p. 19735-19746.
116. Stiuso, P., et al., MicroRNA-423-5p Promotes Autophagy in Cancer Cells and Is Increased in Serum From Hepatocarcinoma Patients Treated With Sorafenib. Mol Ther Nucleic Acids, 2015. 17: p. e233.
117. Pan, B., et al., Mir-24-3p downregulation contributes to VP16–DDP resistance in small-cell lung cancer by targeting ATG4A. Oncotarget, 2015. 6(1): p. 317-331.
118. Kovaleva, V., et al., miRNA-130a Targets ATG2B and DICER1 to Inhibit Autophagy and Trigger Killing of Chronic Lymphocytic Leukemia Cells. Cancer Research, 2012. 72(7): p. 1763-1772.
119. Roccaro, A.M., et al., microRNA-dependent modulation of histone acetylation in Waldenström macroglobulinemia. Blood, 2010. 116(9): p. 1506-1514.
120. Ramalinga, M., et al., MicroRNA-212 negatively regulates starvation induced autophagy in prostate cancer cells by inhibiting SIRT1 and is a modulator of angiogenesis and cellular senescence. Oncotarget, 2015. 6(33): p. 34446-34457.
121. Chen, S., et al., MiR-144 Inhibits Proliferation and Induces Apoptosis and Autophagy in Lung Cancer Cells by Targeting TIGAR. Cellular Physiology and Biochemistry, 2015. 35(3): p. 997-1007.
122. Huang, N., et al., MiR-15a and miR-16 induce autophagy and enhance chemosensitivity of Camptothecin. Cancer Biology & Therapy, 2015. 16(6): p. 941-948.
123. Chen, X., et al., MiR-129 triggers autophagic flux by regulating a novel Notch-1/ E2F7/Beclin-1 axis to impair the viability of human malignant glioma cells. Oncotarget, 2016. 7(8): p. 9222-9235.
124. Yu, X., et al., MiR-214 increases the sensitivity of breast cancer cells to tamoxifen and fulvestrant through inhibition of autophagy. Molecular Cancer, 2015. 14: p. 208.
125. Sun, Q., et al., MiR-200c inhibits autophagy and enhances radiosensitivity in breast cancer cells by targeting UBQLN1. International Journal of Cancer, 2015. 136(5): p. 1003-1012.
126. Zeng, L.-P., et al., miR-222 attenuates cisplatin-induced cell death by targeting the PPP2R2A/Akt/mTOR Axis in bladder cancer cells. Journal of Cellular and Molecular Medicine, 2016. 20(3): p. 559-567.
127. Liu, B., et al., Autophagic pathways as new targets for cancer drug development. Acta Pharmacologica Sinica, 2010. 31(9): p. 1154-1164.
128. Tekirdag, K.A., et al., MIR376 family and cancer. Histol Histopathol., 2016. 4: p. 11752.
129. Rathod, S.S., et al., Tumor suppressive miRNA-34a suppresses cell proliferation and tumor growth of glioma stem cells by targeting Akt and Wnt signaling pathways. FEBS Open Bio, 2014. 4: p. 485-495.
130. Ali, S., et al., Gemcitabine Sensitivity Can Be Induced in Pancreatic Cancer Cells through Modulation of miR-200 and miR-21 Expression by Curcumin or Its Analogue CDF. Cancer research, 2010. 70(9): p. 3606-3617.
131. Chen, J., et al., MicroRNA-130a promotes the metastasis and epithelial-mesenchymal transition of osteosarcoma by targeting PTEN. Oncology Reports, 2016. 35: p. 3285-3292.
132. Gandellini, P., et al., MicroRNAs as new therapeutic targets and tools in cancer. Expert Opinion on Therapeutic Targets, 2011. 15(3): p. 265-279.
133. Seto, A.G., The road toward microRNA therapeutics. The International Journal of Biochemistry & Cell Biology, 2010. 42(8): p. 1298-1305.
134. Liang, X.H., et al., Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature, 1999. 402(6762): p. 672-676.
135. Motoyama, K., et al., Over- and under-expressed microRNAs in human colorectal cancer. International Journal of Oncology, 2009. 34`: p. 1069-1075. .
136. Lin, W.M., et al., Modeling Genomic Diversity and Tumor Dependency in Malignant Melanoma. Cancer Research, 2008. 68(3): p. 664-673.
137. Ma, Y., et al., Biphasic regulation of autophagy by miR-96 in prostate cancer cells under hypoxia. Oncotarget, 2014. 5(19): p. 9169-9182.
138. Wu, C., et al., MiR-30d induces apoptosis and is regulated by the Akt/FOXO pathway in renal cell carcinoma. Cellular Signalling, 2013. 25(5): p. 1212-1221.
139. Esposito, F., et al., Down-Regulation of the miR-25 and miR-30d Contributes to the Development of Anaplastic Thyroid Carcinoma Targeting the Polycomb Protein EZH2. The Journal of Clinical Endocrinology & Metabolism, 2012. 97(5): p. E710-E718.
140. Cao, L.-L., et al., miR-183 inhibits invasion of gastric cancer by targeting Ezrin. International Journal of Clinical and Experimental Pathology, 2014. 7(9): p. 5582-5594.
141. Zhu, J., et al., Down-Regulation of miR-183 Promotes Migration and Invasion of Osteosarcoma by Targeting Ezrin. The American Journal of Pathology, 2012. 180(6): p. 2440-2451.
142. Clerkin, J.S., et al., Mechanisms of ROS modulated cell survival during carcinogenesis. Cancer Letters, 2008. 266(1): p. 30-36.
143. Garg, A.D., et al., ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death. Autophagy, 2013. 9(9): p. 1292-1307.
144. Huang, Q., et al., Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. Autophagy, 2016. 12(6): p. 999-1014.
145. Kroemer, G., G. Mariño, and B. Levine, Autophagy and the integrated stress response. Molecular cell, 2010. 40(2): p. 280-293.
146. Ikeda, Y., et al., Endogenous Drp1 Mediates Mitochondrial Autophagy and Protects the Heart Against Energy Stress Novelty and Significance. Circulation Research, 2015. 116(2): p. 264-278.
147. Ruvolo, P.P., et al., A Functional Role for Mitochondrial Protein Kinase Cα in Bcl2 Phosphorylation and Suppression of Apoptosis. Journal of Biological Chemistry, 1998. 273(39): p. 25436-25442.
148. Blagosklonny, M.V., Unwinding the loop of Bcl-2 phosphorylation. Leukemia., 2001. 15: p. 869-874.
149. Tamura, Y., S. Simizu, and H. Osada, The phosphorylation status and anti-apoptotic activity of Bcl-2 are regulated by ERK and protein phosphatase 2A on the mitochondria. FEBS Letters, 2004. 569(1-3): p. 249-255.
150. Fu, L.-l., et al., MicroRNA-modulated autophagic signaling networks in cancer. The International Journal of Biochemistry & Cell Biology, 2012. 44(5): p. 733-736.
151. Chen, Y., et al., Oncogenic and tumor suppressive roles of microRNAs in apoptosis and autophagy. Apoptosis, 2014. 19(8): p. 1177-1189.
152. Hong, L., et al., MicroRNA-21: a therapeutic target for reversing drug resistance in cancer. Expert Opinion on Therapeutic Targets, 2013. 17(9): p. 1073-1080.
153. Tomimaru, Y., et al., MicroRNA-21 induces resistance to the anti-tumour effect of interferon-alpha/5-fluorouracil in hepatocellular carcinoma cells. Br J Cancer, 2010. 103(10): p. 1617-1626.
154. Li, B., et al., MiR-21 overexpression is associated with acquired resistance of EGFR-TKI in non-small cell lung cancer. Lung Cancer, 2014. 83(2): p. 146-153.
155. Shen, H., et al., Alteration in Mir-21/PTEN Expression Modulates Gefitinib Resistance in Non-Small Cell Lung Cancer. PLOS ONE, 2014. 9(7): p. e103305.
156. Meng, F., et al., MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology, 2007. 133(2): p. 647-658.
157. Connolly, E., et al., Elevated Expression of the miR-17–92 Polycistron and miR-21 in Hepadnavirus-Associated Hepatocellular Carcinoma Contributes to the Malignant Phenotype. The American Journal of Pathology, 2008. 173(3): p. 856-864.
158. Si, M.L., et al., miR-21-mediated tumor growth. Oncogene, 2006. 26(19): p. 2799-2803.
159. He, C., et al., MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN/Akt pathway. Oncotarget, 2015. 6(30): p. 28867-28881.
160. Ueno, T., et al., Loss of Pten, a tumor suppressor, causes the strong inhibition of autophagy without affecting LC3 lipidation. Autophagy, 2008. 4(5): p. 692-700.
161. Iglesias-Bartolome, R. and J.S. Gutkind, Exploiting the mTOR paradox for disease prevention. Oncotarget, 2012. 3(10): p. 1061-1063.
162. Pirrotta, M.T., P. Bernardeschi, and G. Fiorentini, Targeted-therapy in advanced renal cell carcinoma. Curr Med Chem, 2011. 18: p. 1651-1657.
163. Cemma, M., P.K. Kim, and J.H. Brumell, The ubiquitin-binding adaptor proteins p62/SQSTM1 and NDP52 are recruited independently to bacteria-associated microdomains to target Salmonella to the autophagy pathway. Autophagy, 2011. 7(3): p. 341-345.
164. Afanasyeva, E.A., et al., MicroRNA miR-885-5p targets CDK2 and MCM5, activates p53 and inhibits proliferation and survival. Cell Death and Differentiation, 2011. 18(6): p. 974-984.
165. Davila, J.A., et al., Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut, 2005. 54(4): p. 533-539.
166. Ambros, V., The functions of animal microRNAs. Nature, 2004. 431(7006): p. 350-355.
167. Zhang, Z., W. Zheng, and J. Hai, MicroRNA-148b expression is decreased in hepatocellular carcinoma and associated with prognosis. Medical Oncology, 2014. 31(6): p. 984.
168. Han, J., et al., The Drosha-DGCR8 complex in primary microRNA processing. Genes & Development, 2004. 18(24): p. 3016-3027.
169. Huang, Y., et al., MicroRNA-21 gene and cancer. Medical Oncology, 2013. 30(1): p. 376.
170. Zhi, Q., et al., Metastasis-related miR-185 is a potential prognostic biomarker for hepatocellular carcinoma in early stage. Biomedicine & Pharmacotherapy, 2013. 67(5): p. 393-398.
171. Qadir, X.V., et al., miR-185 Inhibits Hepatocellular Carcinoma Growth by Targeting the DNMT1/PTEN/Akt Pathway. The American Journal of Pathology, 2014. 184(8): p. 2355-2364.
172. Zhang, Y., et al., miR-202 suppresses cell proliferation in human hepatocellular carcinoma by downregulating LRP6 post-transcriptionally. FEBS Letters, 2014. 588(10): p. 1913-1920.
173. Wang, J., et al., Downregulation of microRNA-214 and overexpression of FGFR-1 contribute to hepatocellular carcinoma metastasis. Biochemical and Biophysical Research Communications, 2013. 439(1): p. 47-53.
174. Pan, X., Z.-X. Wang, and R. Wang, MicroRNA-21: A novel therapeutic target in human cancer. Cancer Biology & Therapy, 2010. 10(12): p. 1224-1232.
175. Lee, Y., et al., The nuclear RNase III Drosha initiates microRNA processing. Nature, 2003. 425(6956): p. 415-419.
176. Yu, L., et al., MicroRNA-424 Is Down-Regulated in Hepatocellular Carcinoma and Suppresses Cell Migration and Invasion through c-Myb. PLOS ONE, 2014. 9(3): p. e91661.
177. Zhou, L., et al., MicroRNA-21 regulates the migration and invasion of a stem-like population in hepatocellular carcinoma. . International Journal of Oncology, 2013. 43: p. 661-669.
178. Sun, Z., et al., MicroRNA-9 enhances migration and invasion through KLF17 in hepatocellular carcinoma. Molecular Oncology, 2013. 7(5): p. 884-894.
179. Murakami, Y., et al., The expression level of miR-18b in hepatocellular carcinoma is associated with the grade of malignancy and prognosis. BMC Cancer, 2013. 13: p. 99-99.
180. Denli, A.M., et al., Processing of primary microRNAs by the Microprocessor complex. Nature, 2004. 432(7014): p. 231-235.
181. Borchert, G.M., W. Lanier, and B.L. Davidson, RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol, 2006. 13(12): p. 1097-1101.
182. Xiao, F., et al., MicroRNA-503 inhibits the G1/S transition by downregulating cyclin D3 and E2F3 in hepatocellular carcinoma. Journal of Translational Medicine, 2013. 11: p. 195-195.
183. Su, Z.-x., et al., Upregulation of microRNA-25 associates with prognosis in hepatocellular carcinoma. Diagnostic Pathology, 2014. 9: p. 47-47.
184. Li, T., et al., Downregulation of microRNA-139 is associated with hepatocellular carcinoma risk and short-term survival. . Oncology Reports, 2014. 31: p. 1699-1706.
185. Gu, W., X. Li, and J. Wang, miR-139 regulates the proliferation and invasion of hepatocellular carcinoma through the WNT/TCF-4 pathway. Oncology Reports, 2014. 31: p. 397-404.
186. Cai, X., C.H. Hagedorn, and B.R. Cullen, Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA, 2004. 10(12): p. 1957-1966.
187. Weber, B., et al., Methylation of Human MicroRNA Genes in Normal and Neoplastic Cells. Cell Cycle, 2007. 6(9): p. 1001-1005.
188. Scott, G.K., et al., Rapid Alteration of MicroRNA Levels by Histone Deacetylase Inhibition. Cancer Research, 2006. 66(3): p. 1277-1281.
189. Yang, H., et al., Roles of miR‑590-5p and miR-590-3p in the development of hepatocellular carcinoma. Nan Fang Yi Ke Da Xue Xue Bao. , 2013. 33: p. 804-811.
190. Wen, Y., et al., Plasma miRNAs as early biomarkers for detecting hepatocellular carcinoma. International Journal of Cancer, 2015. 137(7): p. 1679-1690.
191. Zhou, J., et al., MicroRNA-127 Post-Transcriptionally Downregulates Sept7 and Suppresses Cell Growth in Hepatocellular Carcinoma Cells. Cellular Physiology and Biochemistry, 2014. 33(5): p. 1537-1546.
192. Klein, U., et al., The DLEU2 miR-15a/16-1 Cluster Controls B Cell Proliferation and Its Deletion Leads to Chronic Lymphocytic Leukemia. Cancer Cell, 2010. 17(1): p. 28-40.
193. Wang, N., et al., MiR-23a-mediated inhibition of topoisomerase 1 expression potentiates cell response to etoposide in human hepatocellular carcinoma. Molecular Cancer, 2013. 12: p. 119-119.
194. Costinean, S., et al., Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in Eμ-miR155 transgenic mice. Proceedings of the National Academy of Sciences of the United States of America, 2006. 103(18): p. 7024-7029.
195. Anwar, S.L. and U. Lehmann, DNA methylation, microRNAs, and their crosstalk as potential biomarkers in hepatocellular carcinoma. World J Gastroenterol, 2014. 20(24): p. 7894-7913.
196. Zhou, L., J. He, and Y. Zhang, MicroRNA-22 expression in hepatocellular carcinoma and its correlation with ezrin protein. Journal of International Medical Research, 2013. 41(4): p. 1009-1016.
197. Liang, X., et al., Histone Demethylase Retinoblastoma Binding Protein 2 is Overexpressed in Hepatocellular Carcinoma and Negatively Regulated by hsa-miR-212. PLoS ONE, 2013. 8(7): p. e69784.
198. Bae, H.J., et al., MicroRNA-29c functions as a tumor suppressor by direct targeting oncogenic SIRT1 in hepatocellular carcinoma. Oncogene, 2014. 33(20): p. 2557-2567.
199. Shen, G., et al., MicroRNA-26b inhibits epithelial-mesenchymal transition in hepatocellular carcinoma by targeting USP9X. BMC Cancer, 2014. 14: p. 393-393.
200. Chen, Z., et al., MiR-27a modulates the MDR1/P-glycoprotein expression by inhibiting FZD7/β-catenin pathway in hepatocellular carcinoma cells. Cellular Signalling, 2013. 25(12): p. 2693-2701.
201. Xie, K., et al., Methylation-associated silencing of microRNA-34b in hepatocellular carcinoma cancer. Gene, 2014. 543(1): p. 101-107.
202. Yang, F., et al., MicroRNA-34a Targets Bcl-2 and Sensitizes Human Hepatocellular Carcinoma Cells to Sorafenib Treatment. Technology in Cancer Research & Treatment, 2014. 13(1): p. 77-86.
203. Dang, Y., et al., Underexpression of miR-34a in Hepatocellular Carcinoma and Its Contribution towards Enhancement of Proliferating Inhibitory Effects of Agents Targeting c-MET. PLoS ONE, 2013. 8(4): p. e61054.
204. Peveling-Oberhag, J., et al., MicroRNA Profiling of Laser-Microdissected Hepatocellular Carcinoma Reveals an Oncogenic Phenotype of the Tumor Capsule. Translational Oncology, 2014. 7(6): p. 672-680.
205. Zhang, J., et al., MiRNA-99a directly regulates AGO2 through translational repression in hepatocellular carcinoma. Oncogenesis, 2014. 3(4): p. e97.
206. Shen, Q., et al., MiR-101 functions as a tumor suppressor by directly targeting nemo-like kinase in liver cancer. Cancer Letters, 2014. 344(2): p. 204-211.
207. Chen, P., X. Zhao, and M. L., Downregulation of microRNA-100 correlates with tumor progression and poor prognosis in hepatocellular carcinoma. . Mol Cell Biochem, 2013. 383: p. 49-58.
208. Zha, R., et al., Genome-Wide Screening Identified That miR-134 Acts as a Metastasis Suppressor by Targeting Integrin β1 in Hepatocellular Carcinoma. PLoS ONE, 2014. 9(2): p. e87665.
209. Lu, Y., et al., MicroRNA-124 suppresses growth of human hepatocellular carcinoma by targeting STAT3. Biochemical and Biophysical Research Communications, 2013. 441(4): p. 873-879.
210. Tsang, F.H., et al., Prognostic Marker MicroRNA-125b Inhibits Tumorigenic Properties of Hepatocellular Carcinoma Cells Via Suppressing Tumorigenic Molecule eIF5A2. Digestive Diseases and Sciences, 2014. 59(10): p. 2477-2487.
211. Ma, Y., et al., miR-24 promotes the proliferation and invasion of HCC cells by targeting SOX7. Tumor Biology, 2014. 35(11): p. 10731-10736.
212. Liu, L.L., et al., FoxD3-regulated microRNA-137 suppresses tumour growth and metastasis in human hepatocellular carcinoma by targeting AKT2. Oncotarget, 2014. 5: p. 5113-5124.
213. Duan, X., et al., MicroRNA-145: a promising biomarker for hepatocellular carcinoma (HCC). Gene, 2014. 541(1): p. 67-68.
214. Liu, Y., et al., MicroRNA-145 inhibits cell proliferation by directly targeting ADAM17 in hepatocellular carcinoma. Oncology Reports, 2014. 32: p. 1923-1930.
215. Noh, J.H., et al., MiR-145 functions as a tumor suppressor by directly targeting histone deacetylase 2 in liver cancer. Cancer Letters, 2013. 335(2): p. 455-462.
216. Amer, M., et al., Hsa-miR-195 targets PCMT1 in hepatocellular carcinoma that increases tumor life span. Tumor Biology, 2014. 35(11): p. 11301-11309.
217. Dai, W., et al., Anti-miR-197 inhibits migration in HCC cells by targeting KAI 1/CD82. Biochemical and Biophysical Research Communications, 2014. 446(2): p. 541-548.
218. Yang, Y.-F., et al., MiR-222 overexpression promotes proliferation of human hepatocellular carcinoma HepG2 cells by downregulating p27. International Journal of Clinical and Experimental Medicine, 2014. 7(4): p. 893-902.
219. Pang, F., et al., MiR-525-3p Enhances the Migration and Invasion of Liver Cancer Cells by Downregulating ZNF395. PLoS ONE, 2014. 9(3): p. e90867.
220. Long, X., et al., MicroRNA-148a is silenced by hypermethylation and interacts with DNA methyltransferase 1 in hepatocellular carcinogenesis. International Journal of Oncology, 2014. 44: p. 1915-1922.
221. Sun, Z., et al., MicroRNA-1246 enhances migration and invasion through CADM1 in hepatocellular carcinoma. BMC Cancer, 2014. 14: p. 616.
222. Llovet, J.M., et al., Design and Endpoints of Clinical Trials in Hepatocellular Carcinoma. JNCI: Journal of the National Cancer Institute, 2008. 100(10): p. 698-711.
223. Mao, B. and G. Wang, MicroRNAs involved with hepatocellular carcinoma (Review). Oncol Rep, 2015. 34(6): p. 2811-2820.
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