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研究生:侯佳妤
研究生(外文):Chia-Yu Hou
論文名稱:miR-101於間葉系基質細胞進行肝細胞分化過程之角色
論文名稱(外文):The role of miR-101 during Hepatogenic Differentiation of Human Mesenchymal Stromal Cells
指導教授:李光申李光申引用關係
指導教授(外文):Oscar K. Lee
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:82
中文關鍵詞:間葉系基質細胞肝細胞分化
外文關鍵詞:miR-101
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MicroRNAs (miRNAs) 為一內生性非轉譯小片段RNA分子,長度約為22個核甘酸。miRNAs可藉由與 mRNA的結合引發mRNA的降解,或抑制目標蛋白質的合成以降低基因的表現。文獻也指出miRNAs可與DNA結合,造成組蛋白的甲基化,進而調節目標基因的表現。miRNAs調控了許多細胞內的生理機制,包括發育、分化、新陳代謝及免疫反應等。人類間葉系基質細胞 (Mesenchymal stromal cells, MSCs)為一成體多能性幹細胞,具有分化成硬骨、軟骨、脂肪甚至源自內胚層的肝細胞之能力。然而在這些分化的過程中,miRNAs所扮演的角色仍然未明。本研究旨在探討人類間葉系幹細胞分化成肝細胞過程中miRNAs可能參與的角色。本實驗依據Agilent miRNAs array分析在不同肝細胞分化時間點的miRNAs 表現情況,結果顯示miR-101在分化過程中的表現量持續上升,此上升的基因表現趨勢也透過real-time PCR驗證。本研究假設miR-101為人類間葉系幹細胞進行分化成肝細胞時的調控分子之一。為檢驗此假設,利用慢病毒送antagomir-101進入人類間葉系幹細胞進行表現,誘導肝細胞分化,再分析其基因表現。結果顯示當抑制了內生性miR-101的表現後,會造成肝細胞分化的特異基因tryptophan 2,3-dioxygenase (TDO2)、 glutamate-ammonia ligase (GLUL)及 serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1(SERPINA1)的基因表現量上升的程度減緩。透過比對Human Genome U133 Plus 2.0 Array基因微陣列分析與miRNAs目標基因預測資料庫miRWalk,STMN1、DDEF1、EZH2、C-MET及Fibronectin1可能為miR-101的目標基因。藉由分析基因表現, STMN1隨著肝細胞分化過程表現量下降,與miR-101的表現量相反;在抑制了內生性miR-101的功能之間葉系基質細胞中,STMN1的相對表現量高於無抑制之載體控制組 (Lenti-pLL3.7) 。STMN1為一19kDa的磷蛋白質,可透過磷酸化作用調控細胞內二級訊息分子,進一步影響細胞的增生、分化與功能。我們利用西方墨點法的方式發現在間葉系基質細胞進行肝細胞分化過程當中,當抑制了內生性miR-101的功能後,STMN1的蛋白質表現量也有被提高的現象,以上實驗結果顯示STMN1可能是此分化過程中miR-101之目標基因。miR-101可能直接調控STMN1的表現而影響肝細胞分化的過程。此研究對於間葉系基質細胞誘導肝細胞分化過程之分子機制探討提供重要資訊。
MicroRNAs (miRNAs) are endogenous non-coding RNAs which comprise about 22 nucleotides. By means of binding to mRNA, miRNAs repress the protein synthesis, or decrease the gene expression by inducing degradation of target mRNAs. Furthermore, miRNAs interact with DNA and induce gene silencing through histone methylation. Through such mechanisms, miRNAs regulate many cellular processes such as development, differentiation, metabolism and immune responses. Human mesenchymal stem cells (hMSCs) are adult multipotent stem cells that can differentiate into osteoblasts, chondrocytes and adipocytes. In recent study, MSCs were demonstrated to be able to trans-differentiate into hetatocytes. However, little is known about the regulation of hepatogenic differentiation (HD) potential by miRNAs. In this study, we aimed to investigate whether miRNAs play a role during HD of hMSCs. Agilent miRNA array was used to detect the expression of miRNA during HD of hMSCs. The result showed the expression of miR-101 increased during HD and this finding was confirmed by real-time PCR. Thus, we hypothesize that miR-101 regulates the HD of MSCs. In order to examine this hypothesis, we lentivirally transduced hMSCs with antagomir-101 to block the endogenous miR-101 prior to inducing HD. Upon repressiong the expression of endogenous miR-101 in hMSCs, the increase of gene expression of hepatic marker, such as tryptophan 2,3-dioxygenase (TDO2), glutamate-ammonia ligase (GLUL) and serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1(SERPINA1) was relatively moderate as compared to control group. By comparing miRNA databases miRWalk with GeneChip® Human Genome U133 Plus 2.0 Array, we identified five potential targets of miR-101, STMN1, DDEF1,c-MET, EZH2 and Fibronecitn 1. From the results of q-PCR , STMN1 is down-regulated during HD of hMSCs. Furthernmore, the result of western blot showed increased expression of STMN1, indicating STMN1 may be the target and regulated by miR-101 during HD of MSCs. Our result showed miR-101 may involve in the modulation of HD of human MSCs by regulating STMN1 expression. This study provides a novel insight into the molecular mechanism by which miRNA regulates the HD of MSCs.
目錄

目錄 II
圖目錄 VI
表格目錄 VIII
Abstract i
摘要 ii
List of abbreviations 1
一、緒論 3
1.1 幹細胞之簡介 3
1.2 成體幹細胞 4
1.3 間葉系基質細胞 4
1.3.1間葉系基質細胞之研究源起 4
1.3.2 間葉系基質細胞之細胞來源 5
1.3.3 間葉系基質細胞之細胞型態與特性 5
1.3.4間葉系基質細胞之分化潛能 7
1.4 肝臟與肝細胞 7
1.4.1 肝臟之結構、細胞組成與功能 7
1.4.2肝臟之疾病與治療 7
1.4.3肝細胞 9
1.4.4 間葉系基質細胞之體外肝細胞分化 9
1.5 microRNAs (miRNAs) 10
1.5.1 miRNAs 之研究起源 10
1.5.2 miRNAs之生合成與功能 10
1.5.3 miRNAs調控幹細胞分化之研究 12
1.5.4 miR-101之簡介 13
1.6 研究目的 13
二、材料與方法 15
2.1細胞培養 15
2.1.1人類間葉系基質細胞 (hBM-MSCs) 的分離與培養 15
2.1.2 293FT cell line 的培養 15
2.2 人類間葉系基質細胞的分化 16
2.2.1肝細胞分化 16
2.2.2成骨細胞分化 16
2.2.3 脂肪細胞分化 16
2.3微陣列 分析 17
2.3.1 肝細胞分化之基因微陣列及其分析 17
2.3.2 肝細胞分化之 microRNA 微陣列及其分析 17
2.4 染色方法 18
2.4.1 PAS (Periodic acid –Schiff) stain 18
2.4.2 Alkaline phosphatase (ALP) stain 18
2.4.3 Von Kossa stain 19
2.5 RNA的抽取與定量、反轉錄 (Reverse transcription, RT) 及即時定量聚合酶鏈鎖反應 (qRT-PCR) 19
2.5.1 Total RNA的抽取與定量 19
2.6 RNA的反轉錄 (Reverse transcription, RT) 及即時定量聚合酶鏈鎖反應 (qRT-PCR) 19
2.6.1 mRNA 19
2.6.2 miRNA 20
2.7 質體的建構 (Construction of Plasmid) 21
2.7.1 Antagomir-101片段的來源 21
2.7.2 確認 pLL3.7 酵素切位的序列正確性 21
2.7.3 準備pLL3.7 21
2.7.4 接合作用 (Ligation) 及轉型作用 (Tansformation) 22
2.7.5 確認 colony 及定序 22
2.8. 慢病毒的製備 (Lentivirus Preparation) 23
2.8.1 慢病毒的包裹 (Lentivirus package) 23
2.8.2 慢病毒的濃縮 (Lentivirus concentration) 23
2.8.3 慢病毒的濃度測定 (Lentivirus titration) 24
2.8.4 慢病毒的轉導 ( Lentivirus transduction) 25
2.9 miR-101目標基因之預測與確認 25
2.10 蛋白質分析 26
2.10.1 細胞蛋白質萃取 26
2.10.2 蛋白質定量 26
2.10.3 西方墨點法 26
2.11 統計分析 27
三、結果 28
3.1 實驗架構 28
3.2 間葉系基質細胞誘導肝細胞分化之miRNA微陣列分析 28
3.3 miR-101於間葉系基質細胞誘導不同lineage細胞分化過程之相對表現量 29
3.4建構表現Antagomir-101之質體並以lentivirus轉導至間葉系基質細胞 30
3.5 間葉系基質細胞誘導肝細胞分化之細胞型態與肝細胞分化標誌基因之表現 31
3.6 miR-101目標基因之預測與確認 32
3.7 miR-101於間葉系基質細胞誘導成骨細胞分化過程之影響 33
四、討論 35
五、結論 40
六、展望 41
七、參考文獻 42
八、圖片與表格 50
九、附錄 82


1 Xie, T. & Spradling, A. C. A niche maintaining germ line stem cells in the Drosophila ovary. Science 290, 328-330 (2000).
2 Li, L. & Xie, T. Stem cell niche: structure and function. Annual review of cell and developmental biology 21, 605-631, doi:10.1146/annurev.cellbio.21.012704.131525 (2005).
3 Ilic, D. & Polak, J. M. Stem cells in regenerative medicine: introduction. British medical bulletin 98, 117-126, doi:10.1093/bmb/ldr012 (2011).
4 Gennero, L. et al. Pluripotent plasticity of stem cells and liver repopulation. Cell biochemistry and function 28, 178-189, doi:10.1002/cbf.1630 (2010).
5 Jiang, Y. et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418, 41-49, doi:10.1038/nature00870 (2002).
6 Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143-147 (1999).
7 Lee, O. K. et al. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood 103, 1669-1675, doi:10.1182/blood-2003-05-1670 (2004).
8 Reynolds, B. A. & Weiss, S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255, 1707-1710 (1992).
9 Rao, M. S. Multipotent and restricted precursors in the central nervous system. The Anatomical record 257, 137-148 (1999).
10 Vodyanik, M. A. et al. A mesoderm-derived precursor for mesenchymal stem and endothelial cells. Cell stem cell 7, 718-729, doi:10.1016/j.stem.2010.11.011 (2010).
11 Friedenstein, A. J. Precursor cells of mechanocytes. International review of cytology 47, 327-359 (1976).
12 Piersma, A. H. et al. Characterization of fibroblastic stromal cells from murine bone marrow. Experimental hematology 13, 237-243 (1985).
13 Prockop, D. J. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276, 71-74 (1997).
14 Caplan, A. I. Mesenchymal stem cells. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 9, 641-650, doi:10.1002/jor.1100090504 (1991).
15 Conget, P. A. & Minguell, J. J. Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells. Journal of cellular physiology 181, 67-73, doi:10.1002/(SICI)1097-4652(199910)181:1<67::AID-JCP7>3.0.CO;2-C (1999).
16 Horwitz, E. M. et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 7, 393-395, doi:10.1080/14653240500319234 (2005).
17 Redzic, A., Smajilagic, A., Aljicevic, M. & Berberovic, L. In vivo osteoinductive effect and in vitro isolation and cultivation bone marrow mesenchymal stem cells. Collegium antropologicum 34, 1405-1409 (2010).
18 Friedenstein, A. J., Piatetzky, S., II & Petrakova, K. V. Osteogenesis in transplants of bone marrow cells. Journal of embryology and experimental morphology 16, 381-390 (1966).
19 Bourin, P. et al. Mesenchymal Progenitor Cells: Tissue Origin, Isolation and Culture. Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie 35, 160-167, doi:10.1159/000124734 (2008).
20 Beresford, J. N., Bennett, J. H., Devlin, C., Leboy, P. S. & Owen, M. E. Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures. Journal of cell science 102 ( Pt 2), 341-351 (1992).
21 Pountos, I. & Giannoudis, P. V. Biology of mesenchymal stem cells. Injury 36 Suppl 3, S8-S12, doi:10.1016/j.injury.2005.07.028 (2005).
22 Tuan, R. S., Boland, G. & Tuli, R. Adult mesenchymal stem cells and cell-based tissue engineering. Arthritis research & therapy 5, 32-45 (2003).
23 Javazon, E. H., Beggs, K. J. & Flake, A. W. Mesenchymal stem cells: paradoxes of passaging. Experimental hematology 32, 414-425, doi:10.1016/j.exphem.2004.02.004 (2004).
24 Bernardo, M. E., Locatelli, F. & Fibbe, W. E. Mesenchymal stromal cells. Annals of the New York Academy of Sciences 1176, 101-117, doi:10.1111/j.1749-6632.2009.04607.x (2009).
25 Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315-317, doi:10.1080/14653240600855905 (2006).
26 Minguell, J. J., Erices, A. & Conget, P. Mesenchymal stem cells. Exp Biol Med (Maywood) 226, 507-520 (2001).
27 Si-Tayeb, K., Lemaigre, F. P. & Duncan, S. A. Organogenesis and development of the liver. Developmental cell 18, 175-189, doi:10.1016/j.devcel.2010.01.011 (2010).
28 Kanematsu, T. & Eguchi, S. Hepatocyte-based bioartificial liver support: past, present and future. Surgery today 28, 483-486 (1998).
29 Tsiaoussis, J., Newsome, P. N., Nelson, L. J., Hayes, P. C. & Plevris, J. N. Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 7, 2-10, doi:10.1053/jlts.2001.20845 (2001).
30 Fox, I. J. & Roy-Chowdhury, J. Hepatocyte transplantation. Journal of hepatology 40, 878-886, doi:10.1016/j.jhep.2004.04.009 (2004).
31 Muraca, M. Evolving concepts in cell therapy of liver disease and current clinical perspectives. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 43, 180-187, doi:10.1016/j.dld.2010.08.007 (2011).
32 Li, J., Li, M., Niu, B. & Gong, J. Therapeutic potential of stem cell in liver regeneration. Frontiers of medicine 5, 26-32, doi:10.1007/s11684-011-0107-0 (2011).
33 Michalopoulos, G. K. & DeFrances, M. C. Liver regeneration. Science 276, 60-66 (1997).
34 Lee, K. D. et al. In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology 40, 1275-1284, doi:10.1002/hep.20469 (2004).
35 Kuo, T. K. et al. Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology 134, 2111-2121, 2121 e2111-2113, doi:10.1053/j.gastro.2008.03.015 (2008).
36 Petersen, B. E. et al. Bone marrow as a potential source of hepatic oval cells. Science 284, 1168-1170 (1999).
37 Alison, M. R. et al. Hepatocytes from non-hepatic adult stem cells. Nature 406, 257, doi:10.1038/35018642 (2000).
38 Schwartz, R. E. et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. The Journal of clinical investigation 109, 1291-1302, doi:10.1172/JCI15182 (2002).
39 Cho, W. C. OncomiRs: the discovery and progress of microRNAs in cancers. Molecular cancer 6, 60, doi:10.1186/1476-4598-6-60 (2007).
40 Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843-854 (1993).
41 Reinhart, B. J. et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901-906, doi:10.1038/35002607 (2000).
42 Griffiths-Jones, S. The microRNA Registry. Nucleic acids research 32, D109-111, doi:10.1093/nar/gkh023 (2004).
43 Winter, J., Jung, S., Keller, S., Gregory, R. I. & Diederichs, S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nature cell biology 11, 228-234, doi:10.1038/ncb0309-228 (2009).
44 Ma, C., Liu, Y. & He, L. MicroRNAs - powerful repression comes from small RNAs. Science in China. Series C, Life sciences / Chinese Academy of Sciences 52, 323-330, doi:10.1007/s11427-009-0056-x (2009).
45 Cullen, B. R. RNAi the natural way. Nature genetics 37, 1163-1165, doi:10.1038/ng1105-1163 (2005).
46 Schwarz, D. S. et al. Asymmetry in the assembly of the RNAi enzyme complex. Cell 115, 199-208 (2003).
47 Khvorova, A., Reynolds, A. & Jayasena, S. D. Functional siRNAs and miRNAs exhibit strand bias. Cell 115, 209-216 (2003).
48 Okamura, K., Ishizuka, A., Siomi, H. & Siomi, M. C. Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways. Genes & development 18, 1655-1666, doi:10.1101/gad.1210204 (2004).
49 Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281-297 (2004).
50 Jackson, R. J. & Standart, N. How do microRNAs regulate gene expression? Science's STKE : signal transduction knowledge environment 2007, re1, doi:10.1126/stke.3672007re1 (2007).
51 Thomas, M., Lieberman, J. & Lal, A. Desperately seeking microRNA targets. Nature structural & molecular biology 17, 1169-1174, doi:10.1038/nsmb.1921 (2010).
52 John, B. et al. Human MicroRNA targets. PLoS biology 2, e363, doi:10.1371/journal.pbio.0020363 (2004).
53 Lewis, B. P., Shih, I. H., Jones-Rhoades, M. W., Bartel, D. P. & Burge, C. B. Prediction of mammalian microRNA targets. Cell 115, 787-798 (2003).
54 Krek, A. et al. Combinatorial microRNA target predictions. Nature genetics 37, 495-500, doi:10.1038/ng1536 (2005).
55 Ichimura, A., Ruike, Y., Terasawa, K. & Tsujimoto, G. miRNAs and regulation of cell signaling. The FEBS journal 278, 1610-1618, doi:10.1111/j.1742-4658.2011.08087.x (2011).
56 Guo, L., Zhao, R. C. & Wu, Y. The role of microRNAs in self-renewal and differentiation of mesenchymal stem cells. Experimental hematology 39, 608-616, doi:10.1016/j.exphem.2011.01.011 (2011).
57 Esquela-Kerscher, A. & Slack, F. J. Oncomirs - microRNAs with a role in cancer. Nature reviews. Cancer 6, 259-269, doi:10.1038/nrc1840 (2006).
58 Liu, S. P. et al. MicroRNAs regulation modulated self-renewal and lineage differentiation of stem cells. Cell transplantation 18, 1039-1045, doi:10.3727/096368909X471224 (2009).
59 Cao, H., Yang, C. S. & Rana, T. M. Evolutionary emergence of microRNAs in human embryonic stem cells. PloS one 3, e2820, doi:10.1371/journal.pone.0002820 (2008).
60 Goff, L. A. et al. Differentiating human multipotent mesenchymal stromal cells regulate microRNAs: prediction of microRNA regulation by PDGF during osteogenesis. Experimental hematology 36, 1354-1369, doi:10.1016/j.exphem.2008.05.004 (2008).
61 Koh, W. et al. Analysis of deep sequencing microRNA expression profile from human embryonic stem cells derived mesenchymal stem cells reveals possible role of let-7 microRNA family in downstream targeting of hepatic nuclear factor 4 alpha. BMC genomics 11 Suppl 1, S6, doi:10.1186/1471-2164-11-S1-S6 (2010).
62 Takagi, S. et al. MicroRNAs regulate human hepatocyte nuclear factor 4alpha, modulating the expression of metabolic enzymes and cell cycle. The Journal of biological chemistry 285, 4415-4422, doi:10.1074/jbc.M109.085431 (2010).
63 Mourelatos, Z. et al. miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs. Genes & development 16, 720-728, doi:10.1101/gad.974702 (2002).
64 Varambally, S. et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 322, 1695-1699, doi:10.1126/science.1165395 (2008).
65 Friedman, J. M. et al. The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2. Cancer research 69, 2623-2629, doi:10.1158/0008-5472.CAN-08-3114 (2009).
66 Li, S. et al. MicroRNA-101 regulates expression of the v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS) oncogene in human hepatocellular carcinoma. Hepatology 49, 1194-1202, doi:10.1002/hep.22757 (2009).
67 Chiang, C. W. et al. PKCalpha mediated induction of miR-101 in human hepatoma HepG2 cells. Journal of biomedical science 17, 35, doi:10.1186/1423-0127-17-35 (2010).
68 Qian, K. et al. Hsa-miR-222 is involved in differentiation of endometrial stromal cells in vitro. Endocrinology 150, 4734-4743, doi:10.1210/en.2008-1629 (2009).
69 Chang, S. J. et al. MicroRNA-34a modulates genes involved in cellular motility and oxidative phosphorylation in neural precursors derived from human umbilical cord mesenchymal stem cells. BMC medical genomics 4, 65, doi:10.1186/1755-8794-4-65 (2011).
70 Naldini, L., Blomer, U., Gage, F. H., Trono, D. & Verma, I. M. Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proceedings of the National Academy of Sciences of the United States of America 93, 11382-11388 (1996).
71 Scherr, M. et al. Lentivirus-mediated antagomir expression for specific inhibition of miRNA function. Nucleic acids research 35, e149, doi:10.1093/nar/gkm971 (2007).
72 Kutner, R. H., Zhang, X. Y. & Reiser, J. Production, concentration and titration of pseudotyped HIV-1-based lentiviral vectors. Nature protocols 4, 495-505, doi:10.1038/nprot.2009.22 (2009).
73 Bocker, W. et al. Quantitative polymerase chain reaction as a reliable method to determine functional lentiviral titer after ex vivo gene transfer in human mesenchymal stem cells. The journal of gene medicine 9, 585-595, doi:10.1002/jgm.1049 (2007).
74 Chang, J. et al. miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1. RNA biology 1, 106-113 (2004).
75 Tzur, G. et al. Comprehensive gene and microRNA expression profiling reveals a role for microRNAs in human liver development. PloS one 4, e7511, doi:10.1371/journal.pone.0007511 (2009).
76 Liu, D. et al. Quantitative analysis of miRNA expression in several developmental stages of human livers. Hepatology research : the official journal of the Japan Society of Hepatology 40, 813-822, doi:10.1111/j.1872-034X.2010.00683.x (2010).
77 Kim, N. et al. Expression profiles of miRNAs in human embryonic stem cells during hepatocyte differentiation. Hepatology research : the official journal of the Japan Society of Hepatology 41, 170-183, doi:10.1111/j.1872-034X.2010.00752.x (2011).
78 Chen, Y. et al. Lentivirus-mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin. Hepatology 46, 200-208, doi:10.1002/hep.21668 (2007).
79 Frankel, L. B. et al. microRNA-101 is a potent inhibitor of autophagy. The EMBO journal 30, 4628-4641, doi:10.1038/emboj.2011.331 (2011).
80 Aoki, R. et al. The polycomb group gene product Ezh2 regulates proliferation and differentiation of murine hepatic stem/progenitor cells. Journal of hepatology 52, 854-863, doi:10.1016/j.jhep.2010.01.027 (2010).
81 Chou, R. H., Yu, Y. L. & Hung, M. C. The roles of EZH2 in cell lineage commitment. American journal of translational research 3, 243-250 (2011).
82 Sobel, A. Stathmin: a relay phosphoprotein for multiple signal transduction? Trends in biochemical sciences 16, 301-305 (1991).
83 Okazaki, T., Himi, T., Peterson, C. & Mori, N. Induction of stathmin mRNA during liver regeneration. FEBS letters 336, 8-12 (1993).
84 Singh, R. Autophagy and regulation of lipid metabolism. Results and problems in cell differentiation 52, 35-46, doi:10.1007/978-3-642-14426-4_4 (2010).
85 Brown, M. T. et al. ASAP1, a phospholipid-dependent arf GTPase-activating protein that associates with and is phosphorylated by Src. Molecular and cellular biology 18, 7038-7051 (1998).
86 Ha, V. L. et al. ASAP3 is a focal adhesion-associated Arf GAP that functions in cell migration and invasion. The Journal of biological chemistry 283, 14915-14926, doi:10.1074/jbc.M709717200 (2008).
87 Pankov, R. & Yamada, K. M. Fibronectin at a glance. Journal of cell science 115, 3861-3863 (2002).
88 Prindull, G. & Zipori, D. Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm. Blood 103, 2892-2899, doi:10.1182/blood-2003-08-2807 (2004).
89 Curmi, P. A. et al. Stathmin and its phosphoprotein family: general properties, biochemical and functional interaction with tubulin. Cell structure and function 24, 345-357 (1999).
90 Rubin, C. I. & Atweh, G. F. The role of stathmin in the regulation of the cell cycle. Journal of cellular biochemistry 93, 242-250, doi:10.1002/jcb.20187 (2004).

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