原癌基因Bmi1在肝癌发生及肝脏干细胞增殖中的作用
摘要
研究目的：原癌基因Bmi1在多种肿瘤类型及干细胞中都有表达,然而该基因在肝癌发生以及肝脏干细胞增殖中的作用尚不清楚。本研究试图明确：1.Bmi1在肝癌发生中的作用及其作用机制；2.Bmi1在肝脏干细胞增殖中的作用。
研究方法：1.我们使用定量PCR和Western杂交检测了Bmi1肝癌组织中的表达,并使用shRNA在肝癌细胞系中抑制Bmi1的表达,从而观察Bmi1缺失对肝癌细胞系生长的影响。接着我们使用高压注射法转染Bmi1和Ras基因到小鼠中,观察Bmi1是否可以结合其它癌基因诱导肝癌发生。最后,我们结合使用肝癌组织,肝癌细胞系及原代细胞,我们分析了Bmi1是否在肝癌发生中调控Ink4A/Arf途径。2.我们利用化合物DDC在小鼠中诱导卵圆细胞增殖建立小鼠模型,通过比较野生型小鼠和Bmi1敲除小鼠中卵圆细胞增殖的差异来分析Bmi1基因对卵圆细胞增殖的影响。
研究结果：1.Bmi1基因在肝细胞肝癌组织及细胞系中都存在过量表达。而当Bmi1的表达被抑制时,细胞生长明显受阻,并且细胞周期不能正常进行。为了明确Bmi1在体内促进肝癌细胞生长的机制,我们稳定表达了Bmi1和／或RasV12,一种Ras的激活形式。我们发现仅有Bmi1或者RasV12不能促进肿瘤在小鼠体内发生。而同时表达Bmi1和Ras V12则可以诱导肿瘤在肝脏中形成。重要的是,我们在体内和体外都没有发现Bmi1抑制Ink4A/Arf的证据。2.Bmi1敲除小鼠中,卵圆细胞,一种可能的肝脏干细胞的增殖存在重要缺陷。在野生型小鼠中,肝脏损失会诱导卵圆细胞大量增殖,而在Bmi1敲除小鼠中,卵圆细胞的增殖数量受到明显抑制。
研究结论：1.Bmi1为肝癌肿瘤细胞生长增殖所必需,而且可以结合其它癌基因诱导肿瘤在肝脏中发生,并且其作用机制不依赖于抑制Ink4A/Arf途径；2.Bmi1为卵圆细胞增殖所必需,是介导肝脏干细胞增殖的一个重要基因。
Objectives:Bmil is a polycomb family proto-oncogene that has been implicated in multiple tumor types. However its role in HCC development and liver stem cell proliferation has not been well-studied. In this study, we are trying to explore the functions of Bmi1 in hepactic carcinogenesis and hepatic stem cell expansion.
Methods:1. We applied qRT-PCR and western blotting to detect the expression of Bmi1 in human HCC tissue. Then we used the shRNA to knock down the expression of Bmi1 in HCC cell lines and to evaluate the impact of loss of Bmi1 on HCC cell growth. To investigate the role of Bmil in promoting liver cancer development in vivo, we stably expressed Bmi1 and/or the activated form of Ras (RasV12) in mouse liver. Mechanism analyis was finished by checking the expression of Ink4A/Arf in human and mice HCC tissues, Bmi1 knock down cell lines and primary mouse hepatocytes.2. To illustrate the role of Bmi1 in maintaining the growth of oval cell, we set up a mouse model. In this mouse model, both Bmi1 WT and KO mice were fed with DDC, a chemical to induce oval cell expansion. By comparing the phenotype of oval cell expansion between Bmi1 WT and Bmi1 KO mice, we can determine the role of Bmi1 in liver stem cell proliferation.
Results:1. We found that Bmi1 is over-expressed in human HCC samples as well as HCC cell lines. When Bmi1 expression is knocked down in human HCC cells lines, it significantly inhibits HCC cell proliferation and perturbs cell cycle regulation. In mouse model, while Bmi1 or RasV12 alone is not sufficient to promote liver cancer development, co-expression of Bmi1 plus RasV12 induces HCC formation in mice. Intriguingly, we found no evidence that Bmi1 inhibits Ink4A/Arf expression in both in vitro and in vivo systems of liver tumor development.2. We found that in Bmi1 null mice, the oval cell, a potential hepatic stem cell, showed decreased proliferation capability. In wild type mice, liver injury resulted from DDC treatment is able to induce marked proliferation of oval cells. In Bmil knock-out mice, however, the cell numbers of oval cell induced by liver injury are decreased due to loss of Bmil.
Conclusions:1. Bmi1 is required for HCC cell proliferation in vitro and it cooperates with other oncogenes to promote hepatic carcinogenesis in vivo. Bmi1 functions as an oncogene independent of Ink4A/Arf repression in liver cancer development; 2. Bmi1 is required for the proliferation of oval cells and is a potential mediator of oval cell expansion in mouse livers.
研究方法：1.我们使用定量PCR和Western杂交检测了Bmi1肝癌组织中的表达,并使用shRNA在肝癌细胞系中抑制Bmi1的表达,从而观察Bmi1缺失对肝癌细胞系生长的影响。接着我们使用高压注射法转染Bmi1和Ras基因到小鼠中,观察Bmi1是否可以结合其它癌基因诱导肝癌发生。最后,我们结合使用肝癌组织,肝癌细胞系及原代细胞,我们分析了Bmi1是否在肝癌发生中调控Ink4A/Arf途径。2.我们利用化合物DDC在小鼠中诱导卵圆细胞增殖建立小鼠模型,通过比较野生型小鼠和Bmi1敲除小鼠中卵圆细胞增殖的差异来分析Bmi1基因对卵圆细胞增殖的影响。
研究结果：1.Bmi1基因在肝细胞肝癌组织及细胞系中都存在过量表达。而当Bmi1的表达被抑制时,细胞生长明显受阻,并且细胞周期不能正常进行。为了明确Bmi1在体内促进肝癌细胞生长的机制,我们稳定表达了Bmi1和／或RasV12,一种Ras的激活形式。我们发现仅有Bmi1或者RasV12不能促进肿瘤在小鼠体内发生。而同时表达Bmi1和Ras V12则可以诱导肿瘤在肝脏中形成。重要的是,我们在体内和体外都没有发现Bmi1抑制Ink4A/Arf的证据。2.Bmi1敲除小鼠中,卵圆细胞,一种可能的肝脏干细胞的增殖存在重要缺陷。在野生型小鼠中,肝脏损失会诱导卵圆细胞大量增殖,而在Bmi1敲除小鼠中,卵圆细胞的增殖数量受到明显抑制。
研究结论：1.Bmi1为肝癌肿瘤细胞生长增殖所必需,而且可以结合其它癌基因诱导肿瘤在肝脏中发生,并且其作用机制不依赖于抑制Ink4A/Arf途径；2.Bmi1为卵圆细胞增殖所必需,是介导肝脏干细胞增殖的一个重要基因。
Objectives:Bmil is a polycomb family proto-oncogene that has been implicated in multiple tumor types. However its role in HCC development and liver stem cell proliferation has not been well-studied. In this study, we are trying to explore the functions of Bmi1 in hepactic carcinogenesis and hepatic stem cell expansion.
Methods:1. We applied qRT-PCR and western blotting to detect the expression of Bmi1 in human HCC tissue. Then we used the shRNA to knock down the expression of Bmi1 in HCC cell lines and to evaluate the impact of loss of Bmi1 on HCC cell growth. To investigate the role of Bmil in promoting liver cancer development in vivo, we stably expressed Bmi1 and/or the activated form of Ras (RasV12) in mouse liver. Mechanism analyis was finished by checking the expression of Ink4A/Arf in human and mice HCC tissues, Bmi1 knock down cell lines and primary mouse hepatocytes.2. To illustrate the role of Bmi1 in maintaining the growth of oval cell, we set up a mouse model. In this mouse model, both Bmi1 WT and KO mice were fed with DDC, a chemical to induce oval cell expansion. By comparing the phenotype of oval cell expansion between Bmi1 WT and Bmi1 KO mice, we can determine the role of Bmi1 in liver stem cell proliferation.
Results:1. We found that Bmi1 is over-expressed in human HCC samples as well as HCC cell lines. When Bmi1 expression is knocked down in human HCC cells lines, it significantly inhibits HCC cell proliferation and perturbs cell cycle regulation. In mouse model, while Bmi1 or RasV12 alone is not sufficient to promote liver cancer development, co-expression of Bmi1 plus RasV12 induces HCC formation in mice. Intriguingly, we found no evidence that Bmi1 inhibits Ink4A/Arf expression in both in vitro and in vivo systems of liver tumor development.2. We found that in Bmi1 null mice, the oval cell, a potential hepatic stem cell, showed decreased proliferation capability. In wild type mice, liver injury resulted from DDC treatment is able to induce marked proliferation of oval cells. In Bmil knock-out mice, however, the cell numbers of oval cell induced by liver injury are decreased due to loss of Bmil.
Conclusions:1. Bmi1 is required for HCC cell proliferation in vitro and it cooperates with other oncogenes to promote hepatic carcinogenesis in vivo. Bmi1 functions as an oncogene independent of Ink4A/Arf repression in liver cancer development; 2. Bmi1 is required for the proliferation of oval cells and is a potential mediator of oval cell expansion in mouse livers.
引文
1. Kensler TW, Qian GS, Chen JG, Groopman JD. Translational strategies for cancer prevention in liver. Nat Rev Cancer 2003;3(5):321-9.
2. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2(9):533-43.
3. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94(2):153-6.
4. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362(9399):1907-17.
5. El-Serag HB, Rudolph KL. Hepatocellular carcinoma:epidemiology and molecular carcinogenesis. Gastroenterology 2007;132(7):2557-76.
6. Feitelson MA, Sun B, Satiroglu Tufan NL, Liu J, Pan J, Lian Z. Genetic mechanisms of hepatocarcinogenesis. Oncogene 2002;21(16):2593-604.
7. Lee S, Lee HJ, Kim JH, Lee HS, Jang JJ, Kang GH. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol 2003;163(4):1371-8.
8. Yang B, Guo M, Herman JG, Clark DP. Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma. Am J Pathol 2003;163(3):1101-7.
9. Okazaki I, Wada N, Nakano M, et al. Difference in gene expression for matrix metalloproteinase-1 between early and advanced hepatocellular carcinomas. Hepatology 1997;25(3):580-4.
10. Ozaki I, Mizuta T, Zhao G, et al. Involvement of the Ets-1 gene in overexpression of matrilysin in human hepatocellular carcinoma. Cancer Res 2000;60(22):6519-25.
11. Chen Q, Seol DW, Carr B, Zarnegar R. Co-expression and regulation of Met and Ron proto-oncogenes in human hepatocellular carcinoma tissues and cell lines. Hepatology 1997;26(1):59-66.
12. Zimonjic DB, Keck CL, Thorgeirsson SS, Popescu NC. Novel recurrent genetic imbalances in human hepatocellular carcinoma cell lines identified by comparative genomic hybridization. Hepatology 1999;29(4):1208-14.
13. Wong N, Lai P, Lee SW, et al. Assessment of genetic changes in hepatocellular carcinoma by comparative genomic hybridization analysis:relationship to disease stage, tumor size, and cirrhosis. Am J Pathol 1999;154(1):37-43.
14. Kitay-Cohen Y, Amiel A, Ashur Y, et al. Analysis of chromosomal aberrations in large hepatocellular carcinomas by comparative genomic hybridization. Cancer Genet Cytogenet 2001;131(1):60-4.
15. Guan XY, Fu SB, Xia JC, et al. Recurrent chromosome changes in 62 primary gastric carcinomas detected by comparative genomic hybridization. Cancer Genet Cytogenet 2000;123(1):27-34.
16. Herath NI, Leggett BA, MacDonald GA. Review of genetic and epigenetic alterations in hepatocarcinogenesis. J Gastroenterol Hepatol 2006;21(1 Pt 1):15-21.
17. Lee JS, Thorgeirsson SS. Genetic profiling of human hepatocellular carcinoma. Semin Liver Dis 2005;25(2):125-32.
18. Tward AD, Jones KD, Yant S, et al. Distinct pathways of genomic progression to benign and malignant tumors of the liver. Proc Natl Acad Sci U S A 2007.
19. Xu CR, Lee S, Ho C, et al. Bmi1 Functions as an Oncogene Independent of Ink4A/Arf Repression in Hepatic Carcinogenesis. Mol Cancer Res 2009;7(12):1937-45.
20. Park IK, Morrison SJ, Clarke MF. Bmi1, stem cells, and senescence regulation. J Clin Invest 2004;113(2):175-9.
21. Lobo NA, Shimono Y, Qian D, Clarke MF. The biology of cancer stem cells. Annu Rev Cell Dev Biol 2007;23:675-99.
22. Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M. Stem cells and cancer; the polycomb connection. Cell 2004;118(4):409-18.
23. Park IK, Qian D, Kiel M, et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 2003;423(6937):302-5.
24. Lessard J, Sauvageau G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 2003;423(6937):255-60.
25. Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 2003;425(6961):962-7.
26. Cui H, Hu B, Li T, et al. Bmi-1 is essential for the tumorigenicity of neuroblastoma cells. Am J Pathol 2007;170(4):1370-8.
27. Leung C, Lingbeek M, Shakhova O, et al. Bmil is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 2004;428(6980):337-41.
28. Vonlanthen S, Heighway J, Altermatt HJ, et al. The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression. Br J Cancer 2001;84(10):1372-6.
29. Kim JH, Yoon SY, Kim CN, et al. The Bmi-1 oncoprotein is overexpressed in human colorectal cancer and correlates with the reduced p16INK4a/p14ARF proteins. Cancer Lett 2004;203(2):217-24.
30. Mihic-Probst D, Kuster A, Kilgus S, et al. Consistent expression of the stem cell renewal factor BMI-1 in primary and metastatic melanoma. Int J Cancer 2007;121(8):1764-70.
31. Sacchi S, Federico M, Dastoli G, et al. Treatment of B-cell non-Hodgkin's lymphoma with anti CD 20 monoclonal antibody Rituximab. Crit Rev Oncol Hematol 2001;37(1):13-25.
32. Kim JH, Yoon SY, Jeong SH, et al. Overexpression of Bmi-1 oncoprotein correlates with axillary lymph node metastases in invasive ductal breast cancer. Breast 2004;13(5):383-8.
33. van Leenders GJ, Dukers D, Hessels D, et al. Polycomb-group oncogenes EZH2, BMI1, and RING1 are overexpressed in prostate cancer with adverse pathologic and clinical features. Eur Urol 2007;52(2):455-63.
34. Liu JH, Song LB, Zhang X, et al. Bmi-1 expression predicts prognosis for patients with gastric carcinoma. J Surg Oncol 2008;97(3):267-72.
35. Dimri GP, Martinez JL, Jacobs JJ, et al. The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells. Cancer Res 2002;62(16):4736-45.
36. Glinsky GV. Death-from-cancer signatures and stem cell contribution to metastatic cancer. Cell Cycle 2005;4(9):1171-5.
37. Hoenerhoff MJ, Chu I, Barkan D, et al. BMI1 cooperates with H-RAS to induce an aggressive breast cancer phenotype with brain metastases. Oncogene 2009;28(34):3022-32.
38. Chiba T, Miyagi S, Saraya A, et al. The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma. Cancer Res 2008;68(19):7742-9.
39. Bracken AP, Kleine-Kohlbrecher D, Dietrich N, et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 2007;21(5):525-30.
40. Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A, van Lohuizen M. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev 1999;13(20):2678-90.
41. Wang H, Pan K, Zhang HK, et al. Increased polycomb-group oncogene Bmi-1 expression correlates with poor prognosis in hepatocellular carcinoma. J Cancer Res Clin Oncol 2008;134(5):535-41.
42. Sasaki M, Ikeda H, Itatsu K, et al. The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma. Lab Invest 2008.
43. Chiba T, Zheng YW, Kita K, et al. Enhanced self-renewal capability in hepatic stem/progenitor cells drives cancer initiation. Gastroenterology 2007;133(3):937-50.
44. Lessard J, Baban S, Sauvageau G. Stage-specific expression of polycomb group genes in human bone marrow cells. Blood 1998;91(4):1216-24.
45. van Lohuizen M, Verbeek S, Scheijen B, Wientjens E, van der Gulden H, Berns A. Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell 1991;65(5):737-52.
46. Alkema MJ, Jacobs H, van Lohuizen M, Berns A. Pertubation of B and T cell development and predisposition to lymphomagenesis in Emu Bmil transgenic mice require the Bmi1 RING finger. Oncogene 1997;15(8):899-910.
47. van der Lugt NM, Domen J, Linders K, et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev 1994;8(7):757-69.
48. Haupt Y, Alexander WS, Barri G, Klinken SP, Adams JM. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell 1991;65(5):753-63.
49. Shinozuka H, Lombardi B, Sell S, Iammarino RM. Early histological and functional alterations of ethionine liver carcinogenesis in rats fed a choline-deficient diet. Cancer Res 1978;38(4):1092-8.
50. Fujio K, Evarts RP, Hu Z, Marsden ER, Thorgeirsson SS. Expression of stem cell factor and its receptor, c-kit, during liver regeneration from putative stem cells in adult rat. Lab Invest 1994;70(4):511-6.
51. Petersen BE, Goff JP, Greenberger JS, Michalopoulos GK. Hepatic oval cells express the hematopoietic stem cell marker Thy-1 in the rat. Hepatology 1998;27(2):433-45.
52. Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells. Science 1988;241(4861):58-62.
53. Baumann U, Crosby HA, Ramani P, Kelly DA, Strain AJ. Expression of the stem cell factor receptor c-kit in normal and diseased pediatric liver:identification of a human hepatic progenitor cell? Hepatology 1999;30(1):112-7.
54. Petersen BE, Grossbard B, Hatch H, Pi L, Deng J, Scott EW. Mouse A6-positive hepatic oval cells also express several hematopoietic stem cell markers. Hepatology 2003;37(3):632-40.
55. Erker L, Grompe M. Signaling networks in hepatic oval cell activation. Stem Cell Res 2007;1(2):90-102.
56. Duncan AW, Dorrell C, Grompe M. Stem cells and liver regeneration. Gastroenterology 2009;137(2):466-81.
57. Chen X, Cheung ST, So S, et al. Gene expression patterns in human liver cancers. Mol Biol Cell 2002;13(6):1929-39.
58. Patil MA, Gutgemann I, Zhang J, et al. Array-based comparative genomic hybridization reveals recurrent chromosomal aberrations and Jab1 as a potential target for 8q gain in hepatocellular carcinoma. Carcinogenesis 2005;26(12):2050-7.
59. Patil MA, Chua MS, Pan KH, et al. An integrated data analysis approach to characterize genes highly expressed in hepatocellular carcinoma. Oncogene 2005;24(23):3737-47.
60. Wojtowicz JM, Kee N. BrdU assay for neurogenesis in rodents. Nat Protoc 2006;1(3):1399-405.
61. Whitfield ML, Sherlock G, Saldanha AJ, et al. Identification of genes periodically expressed in the human cell cycle and their expression in tumors. Mol Biol Cell 2002;13(6):1977-2000.
62. Pardal R, Molofsky AV, He S, Morrison SJ. Stem cell self-renewal and cancer cell proliferation are regulated by common networks that balance the activation of proto-oncogenes and tumor suppressors. Cold Spring Harb Symp Quant Biol 2005;70:177-85.
63. Fasano CA, Dimos JT, Ivanova NB, Lowry N, Lemischka IR, Temple S. shRNA knockdown of Bmi-1 reveals a critical role for p21-Rb pathway in NSC self-renewal during development. Cell Stem Cell 2007;1(1):87-99.
64. Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 1999;397(6715):164-8.
65. Datta S, Hoenerhoff MJ, Bommi P, et al. Bmi-1 cooperates with H-Ras to transform human mammary epithelial cells via dysregulation of multiple growth-regulatory pathways. Cancer Res 2007;67(21):10286-95.
66. Calvisi DF, Ladu S, Gorden A, et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 2006;130(4):1117-28.
67. Harada N, Oshima H, Katoh M, Tamai Y, Oshima M, Taketo MM. Hepatocarcinogenesis in mice with beta-catenin and Ha-ras gene mutations. Cancer Res 2004;64(1):48-54.
68. Lee SA, Ho C, Roy R, et al. Integration of genomic analysis and in vivo transfection to identify sprouty 2 as a candidate tumor suppressor in liver cancer. Hepatology 2007.
69. Zindy F, Williams RT, Baudino TA, et al. Arf tumor suppressor promoter monitors latent oncogenic signals in vivo. Proc Natl Acad Sci U S A 2003;100(26):15930-5.
70. Chen X, Higgins J, Cheung ST, et al. Novel endothelial cell markers in hepatocellular carcinoma. Mod Pathol 2004.
71. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997;88(5):593-602.
72. Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev 1998;12(19):3008-19.
73. Nelsen CJ, Rickheim DG, Tucker MM, Hansen LK, Albrecht JH. Evidence that cyclin D1 mediates both growth and proliferation downstream of TOR in hepatocytes. J Biol Chem 2003;278(6):3656-63.
74. Cheng G, Lewis AE, Meinkoth JL. Ras stimulates aberrant cell cycle progression and apoptosis in rat thyroid cells. Mol Endocrinol 2003;17(3):450-9.
75. Prost S, Sheahan S, Rannie D, Harrison DJ. Adenovirus-mediated Cre deletion of floxed sequences in primary mouse cells is an efficient alternative for studies of gene deletion. Nucleic Acids Res 2001;29(16):E80.
76. Douglas D, Hsu JH, Hung L, et al. BMI-1 promotes ewing sarcoma tumorigenicity independent of CDKN2A repression. Cancer Res 2008;68(16):6507-15.
77. Yu Q, Su B, Liu D, et al. Antisense RNA-mediated suppression of Bmi-1 gene expression inhibits the proliferation of lung cancer cell line A549. Oligonucleotides 2007;17(3):327-35.
78. Wiederschain D, Chen L, Johnson B, et al. Contribution of polycomb homologues Bmi-1 and Mel-18 to medulloblastoma pathogenesis. Mol Cell Biol 2007;27(13):4968-79.
79. Lee K, Adhikary G, Balasubramanian S, et al. Expression of Bmi-1 in epidermis enhances cell survival by altering cell cycle regulatory protein expression and inhibiting apoptosis. J Invest Dermatol 2008;128(1):9-17.
80. Fan C, He L, Kapoor A, et al. Bmi1 promotes prostate tumorigenesis via inhibiting p16(INK4A) and p14(ARF) expression. Biochim Biophys Acta 2008;1782(11):642-8.
81. Dovey JS, Zacharek SJ, Kim CF, Lees JA. Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion. Proc Natl Acad Sci U S A 2008;105(33):11857-62.
82. Tsuda H, Hirohashi S, Shimosato Y, Ino Y, Yoshida T, Terada M. Low incidence of point mutation of c-Ki-ras and N-ras oncogenes in human hepatocellular carcinoma. Jpn J Cancer Res 1989;80(3):196-9.
83. Challen C, Guo K, Collier JD, Cavanagh D, Bassendine MF. Infrequent point mutations in codons 12 and 61 of ras oncogenes in human hepatocellular carcinomas. J Hepatol 1992;14(2-3):342-6.
84. Bruggeman SW, Hulsman D, Tanger E, et al. Bmil controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 2007;12(4):328-41.
85. Liu J, Cao L, Chen J, et al. Bmil regulates mitochondrial function and the DNA damage response pathway. Nature 2009.
1. Kensler TW, Qian GS, Chen JG, Groopman JD. Translational strategies for cancer prevention in liver. Nat Rev Cancer 2003;3(5):321-9.
2. Bruix J, Boix L, Sala M, Llovet JM. Focus on hepatocellular carcinoma. Cancer Cell 2004;5(3):215-9.
3. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics,2002. CA Cancer J Clin 2005;55(2):74-108.
4. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2(9):533-43.
5. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94(2):153-6.
6. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362(9399):1907-17.
7. Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002;31(4):339-46.
8. El-Serag H. Epidemiology of hepatocellular carcinoma. Clinics in Liver Disease 2001;5(1):87-107.
9. El-Serag HB. Hepatocellular carcinoma:an epidemiologic view. J Clin Gastroenterol 2002;35(5 Suppl 2):S72-8.
10. Naugler WE, Sakurai T, Kim S, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007;317(5834):121-4.
11. Evans AA, Chen G, Ross EA, Shen FM, Lin WY, London WT. Eight-year follow-up of the 90,000-person Haimen City cohort:I. Hepatocellular carcinoma mortality, risk factors, and gender differences. Cancer Epidemiol Biomarkers Prev 2002;11(4):369-76.
12. Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002;347(3):168-74.
13. Pollicino T, Squadrito G, Cerenzia G, et al. Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology 2004;126(1):102-10.
14. El-Serag HB, Rudolph KL. Hepatocellular carcinoma:epidemiology and molecular carcinogenesis. Gastroenterology 2007;132(7):2557-76.
15. Feitelson MA, Sun B, Satiroglu Tufan NL, Liu J, Pan J, Lian Z. Genetic mechanisms of hepatocarcinogenesis. Oncogene 2002;21(16):2593-604.
16. Lee S, Lee HJ, Kim JH, Lee HS, Jang JJ, Kang GH. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol 2003;163(4):1371-8.
17. Yang B, Guo M, Herman JG, Clark DP. Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma. Am J Pathol 2003;163(3):1101-7.
18. Okazaki I, Wada N, Nakano M, et al. Difference in gene expression for matrix metalloproteinase-1 between early and advanced hepatocellular carcinomas. Hepatology 1997;25(3):580-4.
19. Ozaki I, Mizuta T, Zhao G, et al. Involvement of the Ets-1 gene in overexpression of matrilysin in human hepatocellular carcinoma. Cancer Res 2000;60(22):6519-25.
20. Chen Q, Seol DW, Carr B, Zarnegar R. Co-expression and regulation of Met and Ron proto-oncogenes in human hepatocellular carcinoma tissues and cell lines. Hepatology 1997;26(1):59-66.
21. Zimonjic DB, Keck CL, Thorgeirsson SS, Popescu NC. Novel recurrent genetic imbalances in human hepatocellular carcinoma cell lines identified by comparative genomic hybridization. Hepatology 1999;29(4):1208-14.
22. Wong N, Lai P, Lee SW, et al. Assessment of genetic changes in hepatocellular carcinoma by comparative genomic hybridization analysis:relationship to disease stage, tumor size, and cirrhosis. Am J Pathol 1999;154(1):37-43.
23. Kitay-Cohen Y, Amiel A, Ashur Y, et al. Analysis of chromosomal aberrations in large hepatocellular carcinomas by comparative genomic hybridization. Cancer Genet Cytogenet 2001;131(1):60-4.
24. Guan XY, Fu SB, Xia JC, et al. Recurrent chromosome changes in 62 primary gastric carcinomas detected by comparative genomic hybridization. Cancer Genet Cytogenet 2000;123(1):27-34.
25. Bressac B, Kew M, Wands J, Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 1991;350(6317):429-31.
26. Buendia MA. Genetics of hepatocellular carcinoma. Semin Cancer Biol 2000;10(3):185-200.
27. Tannapfel A, Busse C, Weinans L, et al. INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. Oncogene 2001;20(48):7104-9.
28. Kondoh N, Wakatsuki T, Hada A, et al. Genetic and epigenetic events in human hepatocarcinogenesis. Int J Oncol 2001;18(6):1271-8.
29. Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 2006;25(27):3787-800.
30. Lee HC, Kim M, Wands JR. Wnt/Frizzled signaling in hepatocellular carcinoma. Front Biosci 2006;11:1901-15.
31. Herath NI, Leggett BA, MacDonald GA. Review of genetic and epigenetic alterations in hepatocarcinogenesis. J Gastroenterol Hepatol 2006;21(1 Pt 1):15-21.
32. Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 2008;48(4):1312-27.
33. Lee JS, Thorgeirsson SS. Genetic profiling of human hepatocellular carcinoma. Semin Liver Dis 2005;25(2):125-32.
34. Felsher DW, Bishop JM. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell 1999;4(2):199-207.
35. Xue W, Zender L, Miething C, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007;445(7128):656-60.
36. Tward AD, Jones KD, Yant S, et al. Distinct pathways of genomic progression to benign and malignant tumors of the liver. Proc Natl Acad Sci U S A 2007.
37. Xu CR, Lee S, Ho C, et al. Bmi1 Functions as an Oncogene Independent of Ink4A/Arf Repression in Hepatic Carcinogenesis. Mol Cancer Res 2009;7(12):1937-45.
38. Park IK, Morrison SJ, Clarke MF. Bmi1, stem cells, and senescence regulation. J Clin Invest 2004;113(2):175-9.
39. Lobo NA, Shimono Y, Qian D, Clarke MF. The biology of cancer stem cells. Annu Rev Cell Dev Biol 2007;23:675-99.
40. Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M. Stem cells and cancer; the polycomb connection. Cell 2004; 118(4):409-18.
41. Alkema MJ, Wiegant J, Raap AK, Berns A, van Lohuizen M. Characterization and chromosomal localization of the human proto-oncogene BMI-1. Hum Mol Genet 1993;2(10):1597-603.
42. Alkema MJ, Bronk M, Verhoeven E, et al. Identification of Bmi1-interacting proteins as constituents of a multimeric mammalian polycomb complex. Genes Dev 1997;11(2):226-40.
43. Alkema MJ, Jacobs H, van Lohuizen M, Berns A. Pertubation of B and T cell development and predisposition to lymphomagenesis in Emu Bmil transgenic mice require the Bmil RING finger. Oncogene 1997;15(8):899-910.
44. Haupt Y, Alexander WS, Barri G, Klinken SP, Adams JM. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell 1991;65(5):753-63.
45. Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A, van Lohuizen M. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev 1999;13(20):2678-90.
46. Park IK, Qian D, Kiel M, et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 2003;423(6937):302-5.
47. Lessard J, Sauvageau G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 2003;423(6937):255-60.
48. Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 2003;425(6961):962-7.
49. Cui H, Hu B, Li T, et al. Bmi-1 is essential for the tumorigenicity of neuroblastoma cells. Am J Pathol 2007;170(4):1370-8.
50. Dimri GP, Martinez JL, Jacobs JJ, et al. The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells. Cancer Res 2002;62(16):4736-45.
51. Leung C, Lingbeek M, Shakhova O, et al. Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 2004;428(6980):337-41.
52. Vonlanthen S, Heighway J, Altermatt HJ, et al. The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression. Br J Cancer 2001;84(10):1372-6.
53. Kim JH, Yoon SY, Kim CN, et al. The Bmi-1 oncoprotein is overexpressed in human colorectal cancer and correlates with the reduced p16INK4a/p14ARF proteins. Cancer Lett 2004;203(2):217-24.
54. Mihic-Probst D, Kuster A, Kilgus S, et al. Consistent expression of the stem cell renewal factor BMI-1 in primary and metastatic melanoma. Int J Cancer 2007;121(8):1764-70.
55. Sacchi S, Federico M, Dastoli G, et al. Treatment of B-cell non-Hodgkin's lymphoma with anti CD 20 monoclonal antibody Rituximab. Crit Rev Oncol Hematol 2001;37(1):13-25.
56. Kim JH, Yoon SY, Jeong SH, et al. Overexpression of Bmi-1 oncoprotein correlates with axillary lymph node metastases in invasive ductal breast cancer. Breast 2004;13(5):383-8.
57. van Leenders GJ, Dukers D, Hessels D, et al. Polycomb-group oncogenes EZH2, BMI1, and RING1 are overexpressed in prostate cancer with adverse pathologic and clinical features. Eur Urol 2007;52(2):455-63.
58. Liu JH, Song LB, Zhang X, et al. Bmi-1 expression predicts prognosis for patients with gastric carcinoma. J Surg Oncol 2008;97(3):267-72.
59. Glinsky GV. Death-from-cancer signatures and stem cell contribution to metastatic cancer. Cell Cycle 2005;4(9):1171-5.
60. Hoenerhoff MJ, Chu I, Barkan D, et al. BMI1 cooperates with H-RAS to induce an aggressive breast cancer phenotype with brain metastases. Oncogene 2009;28(34):3022-32.
61. Chiba T, Miyagi S, Saraya A, et al. The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma. Cancer Res 2008;68(19):7742-9.
62. Lessard J, Baban S, Sauvageau G. Stage-specific expression of polycomb group genes in human bone marrow cells. Blood 1998;91(4):1216-24.
63. van Lohuizen M, Verbeek S, Scheijen B, Wientjens E, van der Gulden H, Berns A. Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell 1991;65(5):737-52.
64. van der Lugt NM, Domen J, Linders K, et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev 1994;8(7):757-69.
65. Itahana K, Zou Y, Itahana Y, et al. Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol Cell Biol 2003;23(l):389-401.
66. Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 1995;83(6):993-1000.
67. Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 1999;397(6715):164-8.
68. Sharpless NE, DePinho RA. The INK4A/ARF locus and its two gene products. Curr Opin Genet Dev 1999;9(1):22-30.
69. Vernell R, Helin K, Muller H. Identification of target genes of the p16INK4A-pRB-E2F pathway. J Biol Chem 2003;278(46):46124-37.
70. Weber JD, Taylor LJ, Roussel MF, Sherr CJ, Bar-Sagi D. Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1999;1(1):20-6.
71. Honda R, Yasuda H. Association of p 19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J 1999;18(1):22-7.
72. Sharpless NE. INK4a/ARF:a multifunctional tumor suppressor locus. Mutat Res 2005;576(1-2):22-38.
73. Ohtani N, Zebedee Z, Huot TJ, et al. Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 2001;409(6823):1067-70.
74. Sreeramaneni R, Chaudhry A, McMahon M, Sherr CJ, Inoue K. Ras-Raf-Arf signaling critically depends on the Dmpl transcription factor. Mol Cell Biol 2005;25(1):220-32.
75. Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell 2006;127(2):265-75.
76. Park NH, Chung YH, Youn KH, et al. Close correlation of p53 mutation to microvascular invasion in hepatocellular carcinoma. J Clin Gastroenterol 2001;33(5):397-401.
77. Lee TK, Man K, Poon RT, Lo CM, Ng IO, Fan ST. Disruption of p53-p21/WAF1 cell cycle pathway contributes to progression and worse clinical outcome of hepatocellular carcinoma. Oncol Rep 2004;12(1):25-31.
78. Bracken AP, Kleine-Kohlbrecher D, Dietrich N, et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 2007;21(5):525-30.
79. Wang H, Pan K, Zhang HK, et al. Increased polycomb-group oncogene Bmi-1 expression correlates with poor prognosis in hepatocellular carcinoma. J Cancer Res Clin Oncol 2008;134(5):535-41.
80. Sasaki M, Ikeda H, Itatsu K, et al. The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma. Lab Invest 2008.
81. Chiba T, Zheng YW, Kita K, et al. Enhanced self-renewal capability in hepatic stem/progenitor cells drives cancer initiation. Gastroenterology 2007;133(3):937-50.
82. Mendez-Vidal C, Wilhelm MT, Hellborg F, Qian W, Wiman KG. The p53-induced mouse zinc finger protein wig-1 binds double-stranded RNA with high affinity. Nucleic Acids Res 2002;30(9):1991-6.
83. TeKippe M, Harrison DE, Chen J. Expansion of hematopoietic stem cell phenotype and activity in Trp53-null mice. Exp Hematol 2003;31(6):521-7.
84. Brenner AJ, Stampfer MR, Aldaz CM. Increased p16 expression with first senescence arrest in human mammary epithelial cells and extended growth capacity with p16 inactivation. Oncogene 1998;17(2):199-205.
85. Wong DJ, Foster SA, Galloway DA, Reid BJ. Progressive region-specific de novo methylation of the p16 CpG island in primary human mammary epithelial cell strains during escape from M(0) growth arrest. Mol Cell Biol 1999;19(8):5642-51.
86. Wu KJ, Grandori C, Amacker M, et al. Direct activation of TERT transcription by c-MYC. Nat Genet 1999;21(2):220-4.
87. Greenberg RA, O'Hagan RC, Deng H, et al. Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation. Oncogene 1999;18(5):1219-26.
2. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2(9):533-43.
3. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94(2):153-6.
4. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362(9399):1907-17.
5. El-Serag HB, Rudolph KL. Hepatocellular carcinoma:epidemiology and molecular carcinogenesis. Gastroenterology 2007;132(7):2557-76.
6. Feitelson MA, Sun B, Satiroglu Tufan NL, Liu J, Pan J, Lian Z. Genetic mechanisms of hepatocarcinogenesis. Oncogene 2002;21(16):2593-604.
7. Lee S, Lee HJ, Kim JH, Lee HS, Jang JJ, Kang GH. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol 2003;163(4):1371-8.
8. Yang B, Guo M, Herman JG, Clark DP. Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma. Am J Pathol 2003;163(3):1101-7.
9. Okazaki I, Wada N, Nakano M, et al. Difference in gene expression for matrix metalloproteinase-1 between early and advanced hepatocellular carcinomas. Hepatology 1997;25(3):580-4.
10. Ozaki I, Mizuta T, Zhao G, et al. Involvement of the Ets-1 gene in overexpression of matrilysin in human hepatocellular carcinoma. Cancer Res 2000;60(22):6519-25.
11. Chen Q, Seol DW, Carr B, Zarnegar R. Co-expression and regulation of Met and Ron proto-oncogenes in human hepatocellular carcinoma tissues and cell lines. Hepatology 1997;26(1):59-66.
12. Zimonjic DB, Keck CL, Thorgeirsson SS, Popescu NC. Novel recurrent genetic imbalances in human hepatocellular carcinoma cell lines identified by comparative genomic hybridization. Hepatology 1999;29(4):1208-14.
13. Wong N, Lai P, Lee SW, et al. Assessment of genetic changes in hepatocellular carcinoma by comparative genomic hybridization analysis:relationship to disease stage, tumor size, and cirrhosis. Am J Pathol 1999;154(1):37-43.
14. Kitay-Cohen Y, Amiel A, Ashur Y, et al. Analysis of chromosomal aberrations in large hepatocellular carcinomas by comparative genomic hybridization. Cancer Genet Cytogenet 2001;131(1):60-4.
15. Guan XY, Fu SB, Xia JC, et al. Recurrent chromosome changes in 62 primary gastric carcinomas detected by comparative genomic hybridization. Cancer Genet Cytogenet 2000;123(1):27-34.
16. Herath NI, Leggett BA, MacDonald GA. Review of genetic and epigenetic alterations in hepatocarcinogenesis. J Gastroenterol Hepatol 2006;21(1 Pt 1):15-21.
17. Lee JS, Thorgeirsson SS. Genetic profiling of human hepatocellular carcinoma. Semin Liver Dis 2005;25(2):125-32.
18. Tward AD, Jones KD, Yant S, et al. Distinct pathways of genomic progression to benign and malignant tumors of the liver. Proc Natl Acad Sci U S A 2007.
19. Xu CR, Lee S, Ho C, et al. Bmi1 Functions as an Oncogene Independent of Ink4A/Arf Repression in Hepatic Carcinogenesis. Mol Cancer Res 2009;7(12):1937-45.
20. Park IK, Morrison SJ, Clarke MF. Bmi1, stem cells, and senescence regulation. J Clin Invest 2004;113(2):175-9.
21. Lobo NA, Shimono Y, Qian D, Clarke MF. The biology of cancer stem cells. Annu Rev Cell Dev Biol 2007;23:675-99.
22. Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M. Stem cells and cancer; the polycomb connection. Cell 2004;118(4):409-18.
23. Park IK, Qian D, Kiel M, et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 2003;423(6937):302-5.
24. Lessard J, Sauvageau G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 2003;423(6937):255-60.
25. Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 2003;425(6961):962-7.
26. Cui H, Hu B, Li T, et al. Bmi-1 is essential for the tumorigenicity of neuroblastoma cells. Am J Pathol 2007;170(4):1370-8.
27. Leung C, Lingbeek M, Shakhova O, et al. Bmil is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 2004;428(6980):337-41.
28. Vonlanthen S, Heighway J, Altermatt HJ, et al. The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression. Br J Cancer 2001;84(10):1372-6.
29. Kim JH, Yoon SY, Kim CN, et al. The Bmi-1 oncoprotein is overexpressed in human colorectal cancer and correlates with the reduced p16INK4a/p14ARF proteins. Cancer Lett 2004;203(2):217-24.
30. Mihic-Probst D, Kuster A, Kilgus S, et al. Consistent expression of the stem cell renewal factor BMI-1 in primary and metastatic melanoma. Int J Cancer 2007;121(8):1764-70.
31. Sacchi S, Federico M, Dastoli G, et al. Treatment of B-cell non-Hodgkin's lymphoma with anti CD 20 monoclonal antibody Rituximab. Crit Rev Oncol Hematol 2001;37(1):13-25.
32. Kim JH, Yoon SY, Jeong SH, et al. Overexpression of Bmi-1 oncoprotein correlates with axillary lymph node metastases in invasive ductal breast cancer. Breast 2004;13(5):383-8.
33. van Leenders GJ, Dukers D, Hessels D, et al. Polycomb-group oncogenes EZH2, BMI1, and RING1 are overexpressed in prostate cancer with adverse pathologic and clinical features. Eur Urol 2007;52(2):455-63.
34. Liu JH, Song LB, Zhang X, et al. Bmi-1 expression predicts prognosis for patients with gastric carcinoma. J Surg Oncol 2008;97(3):267-72.
35. Dimri GP, Martinez JL, Jacobs JJ, et al. The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells. Cancer Res 2002;62(16):4736-45.
36. Glinsky GV. Death-from-cancer signatures and stem cell contribution to metastatic cancer. Cell Cycle 2005;4(9):1171-5.
37. Hoenerhoff MJ, Chu I, Barkan D, et al. BMI1 cooperates with H-RAS to induce an aggressive breast cancer phenotype with brain metastases. Oncogene 2009;28(34):3022-32.
38. Chiba T, Miyagi S, Saraya A, et al. The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma. Cancer Res 2008;68(19):7742-9.
39. Bracken AP, Kleine-Kohlbrecher D, Dietrich N, et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 2007;21(5):525-30.
40. Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A, van Lohuizen M. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev 1999;13(20):2678-90.
41. Wang H, Pan K, Zhang HK, et al. Increased polycomb-group oncogene Bmi-1 expression correlates with poor prognosis in hepatocellular carcinoma. J Cancer Res Clin Oncol 2008;134(5):535-41.
42. Sasaki M, Ikeda H, Itatsu K, et al. The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma. Lab Invest 2008.
43. Chiba T, Zheng YW, Kita K, et al. Enhanced self-renewal capability in hepatic stem/progenitor cells drives cancer initiation. Gastroenterology 2007;133(3):937-50.
44. Lessard J, Baban S, Sauvageau G. Stage-specific expression of polycomb group genes in human bone marrow cells. Blood 1998;91(4):1216-24.
45. van Lohuizen M, Verbeek S, Scheijen B, Wientjens E, van der Gulden H, Berns A. Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell 1991;65(5):737-52.
46. Alkema MJ, Jacobs H, van Lohuizen M, Berns A. Pertubation of B and T cell development and predisposition to lymphomagenesis in Emu Bmil transgenic mice require the Bmi1 RING finger. Oncogene 1997;15(8):899-910.
47. van der Lugt NM, Domen J, Linders K, et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev 1994;8(7):757-69.
48. Haupt Y, Alexander WS, Barri G, Klinken SP, Adams JM. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell 1991;65(5):753-63.
49. Shinozuka H, Lombardi B, Sell S, Iammarino RM. Early histological and functional alterations of ethionine liver carcinogenesis in rats fed a choline-deficient diet. Cancer Res 1978;38(4):1092-8.
50. Fujio K, Evarts RP, Hu Z, Marsden ER, Thorgeirsson SS. Expression of stem cell factor and its receptor, c-kit, during liver regeneration from putative stem cells in adult rat. Lab Invest 1994;70(4):511-6.
51. Petersen BE, Goff JP, Greenberger JS, Michalopoulos GK. Hepatic oval cells express the hematopoietic stem cell marker Thy-1 in the rat. Hepatology 1998;27(2):433-45.
52. Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells. Science 1988;241(4861):58-62.
53. Baumann U, Crosby HA, Ramani P, Kelly DA, Strain AJ. Expression of the stem cell factor receptor c-kit in normal and diseased pediatric liver:identification of a human hepatic progenitor cell? Hepatology 1999;30(1):112-7.
54. Petersen BE, Grossbard B, Hatch H, Pi L, Deng J, Scott EW. Mouse A6-positive hepatic oval cells also express several hematopoietic stem cell markers. Hepatology 2003;37(3):632-40.
55. Erker L, Grompe M. Signaling networks in hepatic oval cell activation. Stem Cell Res 2007;1(2):90-102.
56. Duncan AW, Dorrell C, Grompe M. Stem cells and liver regeneration. Gastroenterology 2009;137(2):466-81.
57. Chen X, Cheung ST, So S, et al. Gene expression patterns in human liver cancers. Mol Biol Cell 2002;13(6):1929-39.
58. Patil MA, Gutgemann I, Zhang J, et al. Array-based comparative genomic hybridization reveals recurrent chromosomal aberrations and Jab1 as a potential target for 8q gain in hepatocellular carcinoma. Carcinogenesis 2005;26(12):2050-7.
59. Patil MA, Chua MS, Pan KH, et al. An integrated data analysis approach to characterize genes highly expressed in hepatocellular carcinoma. Oncogene 2005;24(23):3737-47.
60. Wojtowicz JM, Kee N. BrdU assay for neurogenesis in rodents. Nat Protoc 2006;1(3):1399-405.
61. Whitfield ML, Sherlock G, Saldanha AJ, et al. Identification of genes periodically expressed in the human cell cycle and their expression in tumors. Mol Biol Cell 2002;13(6):1977-2000.
62. Pardal R, Molofsky AV, He S, Morrison SJ. Stem cell self-renewal and cancer cell proliferation are regulated by common networks that balance the activation of proto-oncogenes and tumor suppressors. Cold Spring Harb Symp Quant Biol 2005;70:177-85.
63. Fasano CA, Dimos JT, Ivanova NB, Lowry N, Lemischka IR, Temple S. shRNA knockdown of Bmi-1 reveals a critical role for p21-Rb pathway in NSC self-renewal during development. Cell Stem Cell 2007;1(1):87-99.
64. Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 1999;397(6715):164-8.
65. Datta S, Hoenerhoff MJ, Bommi P, et al. Bmi-1 cooperates with H-Ras to transform human mammary epithelial cells via dysregulation of multiple growth-regulatory pathways. Cancer Res 2007;67(21):10286-95.
66. Calvisi DF, Ladu S, Gorden A, et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 2006;130(4):1117-28.
67. Harada N, Oshima H, Katoh M, Tamai Y, Oshima M, Taketo MM. Hepatocarcinogenesis in mice with beta-catenin and Ha-ras gene mutations. Cancer Res 2004;64(1):48-54.
68. Lee SA, Ho C, Roy R, et al. Integration of genomic analysis and in vivo transfection to identify sprouty 2 as a candidate tumor suppressor in liver cancer. Hepatology 2007.
69. Zindy F, Williams RT, Baudino TA, et al. Arf tumor suppressor promoter monitors latent oncogenic signals in vivo. Proc Natl Acad Sci U S A 2003;100(26):15930-5.
70. Chen X, Higgins J, Cheung ST, et al. Novel endothelial cell markers in hepatocellular carcinoma. Mod Pathol 2004.
71. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997;88(5):593-602.
72. Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev 1998;12(19):3008-19.
73. Nelsen CJ, Rickheim DG, Tucker MM, Hansen LK, Albrecht JH. Evidence that cyclin D1 mediates both growth and proliferation downstream of TOR in hepatocytes. J Biol Chem 2003;278(6):3656-63.
74. Cheng G, Lewis AE, Meinkoth JL. Ras stimulates aberrant cell cycle progression and apoptosis in rat thyroid cells. Mol Endocrinol 2003;17(3):450-9.
75. Prost S, Sheahan S, Rannie D, Harrison DJ. Adenovirus-mediated Cre deletion of floxed sequences in primary mouse cells is an efficient alternative for studies of gene deletion. Nucleic Acids Res 2001;29(16):E80.
76. Douglas D, Hsu JH, Hung L, et al. BMI-1 promotes ewing sarcoma tumorigenicity independent of CDKN2A repression. Cancer Res 2008;68(16):6507-15.
77. Yu Q, Su B, Liu D, et al. Antisense RNA-mediated suppression of Bmi-1 gene expression inhibits the proliferation of lung cancer cell line A549. Oligonucleotides 2007;17(3):327-35.
78. Wiederschain D, Chen L, Johnson B, et al. Contribution of polycomb homologues Bmi-1 and Mel-18 to medulloblastoma pathogenesis. Mol Cell Biol 2007;27(13):4968-79.
79. Lee K, Adhikary G, Balasubramanian S, et al. Expression of Bmi-1 in epidermis enhances cell survival by altering cell cycle regulatory protein expression and inhibiting apoptosis. J Invest Dermatol 2008;128(1):9-17.
80. Fan C, He L, Kapoor A, et al. Bmi1 promotes prostate tumorigenesis via inhibiting p16(INK4A) and p14(ARF) expression. Biochim Biophys Acta 2008;1782(11):642-8.
81. Dovey JS, Zacharek SJ, Kim CF, Lees JA. Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion. Proc Natl Acad Sci U S A 2008;105(33):11857-62.
82. Tsuda H, Hirohashi S, Shimosato Y, Ino Y, Yoshida T, Terada M. Low incidence of point mutation of c-Ki-ras and N-ras oncogenes in human hepatocellular carcinoma. Jpn J Cancer Res 1989;80(3):196-9.
83. Challen C, Guo K, Collier JD, Cavanagh D, Bassendine MF. Infrequent point mutations in codons 12 and 61 of ras oncogenes in human hepatocellular carcinomas. J Hepatol 1992;14(2-3):342-6.
84. Bruggeman SW, Hulsman D, Tanger E, et al. Bmil controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 2007;12(4):328-41.
85. Liu J, Cao L, Chen J, et al. Bmil regulates mitochondrial function and the DNA damage response pathway. Nature 2009.
1. Kensler TW, Qian GS, Chen JG, Groopman JD. Translational strategies for cancer prevention in liver. Nat Rev Cancer 2003;3(5):321-9.
2. Bruix J, Boix L, Sala M, Llovet JM. Focus on hepatocellular carcinoma. Cancer Cell 2004;5(3):215-9.
3. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics,2002. CA Cancer J Clin 2005;55(2):74-108.
4. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2(9):533-43.
5. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94(2):153-6.
6. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362(9399):1907-17.
7. Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002;31(4):339-46.
8. El-Serag H. Epidemiology of hepatocellular carcinoma. Clinics in Liver Disease 2001;5(1):87-107.
9. El-Serag HB. Hepatocellular carcinoma:an epidemiologic view. J Clin Gastroenterol 2002;35(5 Suppl 2):S72-8.
10. Naugler WE, Sakurai T, Kim S, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007;317(5834):121-4.
11. Evans AA, Chen G, Ross EA, Shen FM, Lin WY, London WT. Eight-year follow-up of the 90,000-person Haimen City cohort:I. Hepatocellular carcinoma mortality, risk factors, and gender differences. Cancer Epidemiol Biomarkers Prev 2002;11(4):369-76.
12. Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002;347(3):168-74.
13. Pollicino T, Squadrito G, Cerenzia G, et al. Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology 2004;126(1):102-10.
14. El-Serag HB, Rudolph KL. Hepatocellular carcinoma:epidemiology and molecular carcinogenesis. Gastroenterology 2007;132(7):2557-76.
15. Feitelson MA, Sun B, Satiroglu Tufan NL, Liu J, Pan J, Lian Z. Genetic mechanisms of hepatocarcinogenesis. Oncogene 2002;21(16):2593-604.
16. Lee S, Lee HJ, Kim JH, Lee HS, Jang JJ, Kang GH. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol 2003;163(4):1371-8.
17. Yang B, Guo M, Herman JG, Clark DP. Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma. Am J Pathol 2003;163(3):1101-7.
18. Okazaki I, Wada N, Nakano M, et al. Difference in gene expression for matrix metalloproteinase-1 between early and advanced hepatocellular carcinomas. Hepatology 1997;25(3):580-4.
19. Ozaki I, Mizuta T, Zhao G, et al. Involvement of the Ets-1 gene in overexpression of matrilysin in human hepatocellular carcinoma. Cancer Res 2000;60(22):6519-25.
20. Chen Q, Seol DW, Carr B, Zarnegar R. Co-expression and regulation of Met and Ron proto-oncogenes in human hepatocellular carcinoma tissues and cell lines. Hepatology 1997;26(1):59-66.
21. Zimonjic DB, Keck CL, Thorgeirsson SS, Popescu NC. Novel recurrent genetic imbalances in human hepatocellular carcinoma cell lines identified by comparative genomic hybridization. Hepatology 1999;29(4):1208-14.
22. Wong N, Lai P, Lee SW, et al. Assessment of genetic changes in hepatocellular carcinoma by comparative genomic hybridization analysis:relationship to disease stage, tumor size, and cirrhosis. Am J Pathol 1999;154(1):37-43.
23. Kitay-Cohen Y, Amiel A, Ashur Y, et al. Analysis of chromosomal aberrations in large hepatocellular carcinomas by comparative genomic hybridization. Cancer Genet Cytogenet 2001;131(1):60-4.
24. Guan XY, Fu SB, Xia JC, et al. Recurrent chromosome changes in 62 primary gastric carcinomas detected by comparative genomic hybridization. Cancer Genet Cytogenet 2000;123(1):27-34.
25. Bressac B, Kew M, Wands J, Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 1991;350(6317):429-31.
26. Buendia MA. Genetics of hepatocellular carcinoma. Semin Cancer Biol 2000;10(3):185-200.
27. Tannapfel A, Busse C, Weinans L, et al. INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. Oncogene 2001;20(48):7104-9.
28. Kondoh N, Wakatsuki T, Hada A, et al. Genetic and epigenetic events in human hepatocarcinogenesis. Int J Oncol 2001;18(6):1271-8.
29. Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 2006;25(27):3787-800.
30. Lee HC, Kim M, Wands JR. Wnt/Frizzled signaling in hepatocellular carcinoma. Front Biosci 2006;11:1901-15.
31. Herath NI, Leggett BA, MacDonald GA. Review of genetic and epigenetic alterations in hepatocarcinogenesis. J Gastroenterol Hepatol 2006;21(1 Pt 1):15-21.
32. Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 2008;48(4):1312-27.
33. Lee JS, Thorgeirsson SS. Genetic profiling of human hepatocellular carcinoma. Semin Liver Dis 2005;25(2):125-32.
34. Felsher DW, Bishop JM. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell 1999;4(2):199-207.
35. Xue W, Zender L, Miething C, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007;445(7128):656-60.
36. Tward AD, Jones KD, Yant S, et al. Distinct pathways of genomic progression to benign and malignant tumors of the liver. Proc Natl Acad Sci U S A 2007.
37. Xu CR, Lee S, Ho C, et al. Bmi1 Functions as an Oncogene Independent of Ink4A/Arf Repression in Hepatic Carcinogenesis. Mol Cancer Res 2009;7(12):1937-45.
38. Park IK, Morrison SJ, Clarke MF. Bmi1, stem cells, and senescence regulation. J Clin Invest 2004;113(2):175-9.
39. Lobo NA, Shimono Y, Qian D, Clarke MF. The biology of cancer stem cells. Annu Rev Cell Dev Biol 2007;23:675-99.
40. Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M. Stem cells and cancer; the polycomb connection. Cell 2004; 118(4):409-18.
41. Alkema MJ, Wiegant J, Raap AK, Berns A, van Lohuizen M. Characterization and chromosomal localization of the human proto-oncogene BMI-1. Hum Mol Genet 1993;2(10):1597-603.
42. Alkema MJ, Bronk M, Verhoeven E, et al. Identification of Bmi1-interacting proteins as constituents of a multimeric mammalian polycomb complex. Genes Dev 1997;11(2):226-40.
43. Alkema MJ, Jacobs H, van Lohuizen M, Berns A. Pertubation of B and T cell development and predisposition to lymphomagenesis in Emu Bmil transgenic mice require the Bmil RING finger. Oncogene 1997;15(8):899-910.
44. Haupt Y, Alexander WS, Barri G, Klinken SP, Adams JM. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell 1991;65(5):753-63.
45. Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A, van Lohuizen M. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev 1999;13(20):2678-90.
46. Park IK, Qian D, Kiel M, et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 2003;423(6937):302-5.
47. Lessard J, Sauvageau G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 2003;423(6937):255-60.
48. Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 2003;425(6961):962-7.
49. Cui H, Hu B, Li T, et al. Bmi-1 is essential for the tumorigenicity of neuroblastoma cells. Am J Pathol 2007;170(4):1370-8.
50. Dimri GP, Martinez JL, Jacobs JJ, et al. The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells. Cancer Res 2002;62(16):4736-45.
51. Leung C, Lingbeek M, Shakhova O, et al. Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 2004;428(6980):337-41.
52. Vonlanthen S, Heighway J, Altermatt HJ, et al. The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression. Br J Cancer 2001;84(10):1372-6.
53. Kim JH, Yoon SY, Kim CN, et al. The Bmi-1 oncoprotein is overexpressed in human colorectal cancer and correlates with the reduced p16INK4a/p14ARF proteins. Cancer Lett 2004;203(2):217-24.
54. Mihic-Probst D, Kuster A, Kilgus S, et al. Consistent expression of the stem cell renewal factor BMI-1 in primary and metastatic melanoma. Int J Cancer 2007;121(8):1764-70.
55. Sacchi S, Federico M, Dastoli G, et al. Treatment of B-cell non-Hodgkin's lymphoma with anti CD 20 monoclonal antibody Rituximab. Crit Rev Oncol Hematol 2001;37(1):13-25.
56. Kim JH, Yoon SY, Jeong SH, et al. Overexpression of Bmi-1 oncoprotein correlates with axillary lymph node metastases in invasive ductal breast cancer. Breast 2004;13(5):383-8.
57. van Leenders GJ, Dukers D, Hessels D, et al. Polycomb-group oncogenes EZH2, BMI1, and RING1 are overexpressed in prostate cancer with adverse pathologic and clinical features. Eur Urol 2007;52(2):455-63.
58. Liu JH, Song LB, Zhang X, et al. Bmi-1 expression predicts prognosis for patients with gastric carcinoma. J Surg Oncol 2008;97(3):267-72.
59. Glinsky GV. Death-from-cancer signatures and stem cell contribution to metastatic cancer. Cell Cycle 2005;4(9):1171-5.
60. Hoenerhoff MJ, Chu I, Barkan D, et al. BMI1 cooperates with H-RAS to induce an aggressive breast cancer phenotype with brain metastases. Oncogene 2009;28(34):3022-32.
61. Chiba T, Miyagi S, Saraya A, et al. The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma. Cancer Res 2008;68(19):7742-9.
62. Lessard J, Baban S, Sauvageau G. Stage-specific expression of polycomb group genes in human bone marrow cells. Blood 1998;91(4):1216-24.
63. van Lohuizen M, Verbeek S, Scheijen B, Wientjens E, van der Gulden H, Berns A. Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell 1991;65(5):737-52.
64. van der Lugt NM, Domen J, Linders K, et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev 1994;8(7):757-69.
65. Itahana K, Zou Y, Itahana Y, et al. Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol Cell Biol 2003;23(l):389-401.
66. Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 1995;83(6):993-1000.
67. Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 1999;397(6715):164-8.
68. Sharpless NE, DePinho RA. The INK4A/ARF locus and its two gene products. Curr Opin Genet Dev 1999;9(1):22-30.
69. Vernell R, Helin K, Muller H. Identification of target genes of the p16INK4A-pRB-E2F pathway. J Biol Chem 2003;278(46):46124-37.
70. Weber JD, Taylor LJ, Roussel MF, Sherr CJ, Bar-Sagi D. Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1999;1(1):20-6.
71. Honda R, Yasuda H. Association of p 19(ARF) with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53. EMBO J 1999;18(1):22-7.
72. Sharpless NE. INK4a/ARF:a multifunctional tumor suppressor locus. Mutat Res 2005;576(1-2):22-38.
73. Ohtani N, Zebedee Z, Huot TJ, et al. Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 2001;409(6823):1067-70.
74. Sreeramaneni R, Chaudhry A, McMahon M, Sherr CJ, Inoue K. Ras-Raf-Arf signaling critically depends on the Dmpl transcription factor. Mol Cell Biol 2005;25(1):220-32.
75. Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell 2006;127(2):265-75.
76. Park NH, Chung YH, Youn KH, et al. Close correlation of p53 mutation to microvascular invasion in hepatocellular carcinoma. J Clin Gastroenterol 2001;33(5):397-401.
77. Lee TK, Man K, Poon RT, Lo CM, Ng IO, Fan ST. Disruption of p53-p21/WAF1 cell cycle pathway contributes to progression and worse clinical outcome of hepatocellular carcinoma. Oncol Rep 2004;12(1):25-31.
78. Bracken AP, Kleine-Kohlbrecher D, Dietrich N, et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 2007;21(5):525-30.
79. Wang H, Pan K, Zhang HK, et al. Increased polycomb-group oncogene Bmi-1 expression correlates with poor prognosis in hepatocellular carcinoma. J Cancer Res Clin Oncol 2008;134(5):535-41.
80. Sasaki M, Ikeda H, Itatsu K, et al. The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma. Lab Invest 2008.
81. Chiba T, Zheng YW, Kita K, et al. Enhanced self-renewal capability in hepatic stem/progenitor cells drives cancer initiation. Gastroenterology 2007;133(3):937-50.
82. Mendez-Vidal C, Wilhelm MT, Hellborg F, Qian W, Wiman KG. The p53-induced mouse zinc finger protein wig-1 binds double-stranded RNA with high affinity. Nucleic Acids Res 2002;30(9):1991-6.
83. TeKippe M, Harrison DE, Chen J. Expansion of hematopoietic stem cell phenotype and activity in Trp53-null mice. Exp Hematol 2003;31(6):521-7.
84. Brenner AJ, Stampfer MR, Aldaz CM. Increased p16 expression with first senescence arrest in human mammary epithelial cells and extended growth capacity with p16 inactivation. Oncogene 1998;17(2):199-205.
85. Wong DJ, Foster SA, Galloway DA, Reid BJ. Progressive region-specific de novo methylation of the p16 CpG island in primary human mammary epithelial cell strains during escape from M(0) growth arrest. Mol Cell Biol 1999;19(8):5642-51.
86. Wu KJ, Grandori C, Amacker M, et al. Direct activation of TERT transcription by c-MYC. Nat Genet 1999;21(2):220-4.
87. Greenberg RA, O'Hagan RC, Deng H, et al. Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation. Oncogene 1999;18(5):1219-26.