Huh-7 Human Liver Cancer Cells: A Model System to Understand Hepatocellular Carcinoma and Therapy

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ABSTRACT

In the last decades, the use of in vitro systems in liver research has grown exponentially. Important reasons promoting this work are the high throughput and ease of genetic manipulations afforded by these experiments relative to in vivo experiments. Thousands of investigations of hepatocellular carcinoma have been performed employing the human hepatoma Huh-7 cell line. The extensive body of knowledge produced attests to the importance and value of this in vitro cell system to study the characteristics of hepatomas and the potential of natural and synthetic compounds to prevent and eliminate this liver cancer. The necessarily brief summary provided here attempts to summarise some of the most recent achievements and limitations of investigations with Huh-7 cells and derivatives.

Cite this paper

A. Krelle, A. Okoli and G. Mendz, "Huh-7 Human Liver Cancer Cells: A Model System to Understand Hepatocellular Carcinoma and Therapy," Journal of Cancer Therapy, Vol. 4 No. 2, 2013, pp. 606-631. doi: 10.4236/jct.2013.42078.

References

[1] [1] D. M. Parkin, “The Global Health Burden of InfectionAssociated Cancers in the Year 2002,” International Journal of Cancer, Vol. 118, No. 12, 2006, pp. 3030-3044. doi:10.1002/ijc.21731
[2] R. Bartenschlager and V. Lohmann, “Replication of Hepatitis C Virus,” Journal of General Virology, Vol. 81, No. 7, 2000, pp. 1631-1648.
[3] V. Lohmann, F. Korner, J. Koch, U. Herian, L. Theilmann, et al., “Replication of Subgenomic Hepatitis C Virus RNAs in a Hepatoma Cell Line,” Science, Vol. 285, No. 5424, 1999, pp. 110-113. doi:10.1126/science.285.5424.110
[4] T. Date, T. Kato, M. Miyamoto, Z. Zhao, K. Yasui, et al., “Genotype 2a Hepatitis C Virus Subgenomic Replicon can Replicate in HepG2 and IMY-N9 cells,” Journal of Biological Chemistry, Vol. 279, No. 21, 2004, pp. 22371-22376. doi:10.1074/jbc.M311120200
[5] K. S. Chang, Z. Cai, C. Zhang, G. C. Sen, B. R. Williams, et al., “Replication of Hepatitis C Virus (HCV) RNA in Mouse Embryonic Fibroblasts: Protein Kinase R (PKR)Dependent and PKR-Independent Mechanisms for Controlling HCV RNA Replication and Mediating Interferon Activities,” Journal of Virology, Vol. 80, No. 15, 2006, pp. 7364-7374. doi:10.1128/JVI.00586-06
[6] T. Kato, T. Date, M. Miyamoto, Z. Zhao, M. Mizokami, et al., “Nonhepatic Cell Lines HeLa and 293 Support Efficient Replication of the Hepatitis C Virus Genotype 2a Subgenomic Replicon,” Journal of Virology, Vol. 79, No. 1, 2005, pp. 592-596. doi:10.1128/JVI.79.1.592-596.2005
[7] H. Nakabayashi, , K. Taketa, K. Miyano, T. Yamane and J. Sato, “Growth of Human Hepatoma Cells Lines with Differentiated Functions in Chemically Defined Medium,” Cancer Research, Vol. 42, No. 9, 1982, pp. 3858-3863.
[8] I. Doi, “Establishment of a Cell Line and Its Clonal Sublines from a Patient with Hepatoblastoma,” Gann, Vol. 67, No. 1, 1976, pp. 1-10.
[9] J. J. Alexander, E. M. Bey, E. W. Geddes and G. Lecatsas, “Establishment of a Continuously Growing Cell Line from Primary Carcinoma of the Liver,” Sout African Medical Journal, Vol. 50, No. 54, 1976, pp. 2124-2128.
[10] G. M. MacNab, J. J. Alexander, G. Lecatsas, E. M. Bey and J. M. Urbanowicz, “Hepatitis B Surface Antigen Produced by a Human Hepatoma Cell Line,” British Journal of Cancer, Vol. 34, No. 5, 1976, pp. 509-515. doi:10.1038/bjc.1976.205
[11] D. P. Aden, A. Fogel, S. Plotkin, I. Damjanov and B. B. Knowles, “Controlled Synthesis of HBsAg in a Differentiated Human Liver Carcinoma-Derived Cell Line,” Nature, Vol. 282, No. 5739, 1979, pp. 615-616. doi:10.1038/282615a0
[12] N. Huh, and T. Utakoji, “Production of HBs-Antigen by Two New Human Hepatoma Cell Lines and Its Enhancement by Dexamethasone,” Gann, Vol. 72, No. 1, 1981, pp. 178-179.
[13] H. Nakamura, Y. Izumoto, H. Kambe, T. Kuroda, T. Mori, et al., “Molecular Cloning of Complementary DNA for a Novel Human Hepatoma-Derived Growth Factor. Its Homology with High Mobility Group-1 Protein,” Journal of Biological Chemistry, Vol. 269, No. 40, 1994, pp. 25143-25149.
[14] M. Triyatni, E. A. Berger and B. Saunier, “A New Model to Produce Infectious Hepatitis C Virus without the Replication Requirement,” PLoS Pathogens, Vol. 7, No. 4, 2011, p. e1001333. doi:10.1371/journal.ppat.1001333
[15] H. Tang, L. Liu L, F. J. Liu, E. Q. Chen, S. Murakami, et al., “Establishment of Cell Lines Using a DoxycyclineInducible Gene Expression System to Regulate Expression of Hepatitis B Virus X Protein,” Archives of Virology, Vol. 154, No. 7, 2009, pp. 1021-1026. doi:10.1007/s00705-009-0402-0
[16] B. B. Knowles, C. C. Howe and D. P. Aden, “Human Hepatocellular Carcinoma Cell Lines Secrete the Major Plasma Proteins and Hepatitis B Surface Antigen,” Science, Vol. 209, 1980, pp. 497-499.
[17] W. K. Kim, Y. J. In, J. H. Kim, H. J. Cho, J. H. Kim, et al., “Quantitative Relationship of Dioxin-Responsive Gene Expression to Dioxin Response Element in Hep3B and HepG2 Human Hepatocarcinoma Cell Lines,” Toxicology Letters, Vol. 165, No. 2, 2006, pp. 174-181. doi:10.1016/j.toxlet.2006.03.007
[18] C. Jiang, B. Zhou, K. Fan, E. Heung, L. Xue, et al., “A Sequential Treatment of Depsipeptide followed by 5-Azacytidine Enhances Gadd45beta Expression in Hepatocellular Carcinoma Cells,” Anticancer Research, Vol. 27, No. 6B, 2007, pp. 3783-3789.
[19] J. Lin, L. Schyschka, R. Muhl-Benninghaus, J. Neumann, L. Hao, et al., “Comparative Analysis of Phase I and II Enzyme Activities in 5 Hepatic Cell Lines Identifies Huh-7 and HCC-T Cells with the Highest Potential to Study Drug metabolism,” Archives of Toxicology, Vol. 86, No. 1, 2012, pp. 87-95. doi:10.1007/s00204-011-0733-y
[20] V. Mersch-Sundermann, S. Knasmuller, X. J. Wu, F. Darroudi and F. Kassie, “Use of a Human-Derived Liver Cell Line for the Detection of Cytoprotective, Antigenotoxic and Cogenotoxic agents,” Toxicology, Vol. 198, No. 1-3, 2004, pp. 329-340. doi:10.1016/j.tox.2004.02.009
[21] S. Locarnini and F. Zoulim, “Molecular Genetics of HBV Infection,” Antiviral Therapy, Vol. 15, Suppl. 3, 2010, pp. 3-14. doi:10.3851/IMP1619
[22] M. Bharadwaj, G. Roy, K. Dutta K, M. Misbah, M. Husain M and S. Hussain, “Tackling Hepatitis B VirusAssociated Hepatocellular Carcinoma—The Future is Now,” Cancer and Metastasis Reviews, 2012. doi:10.1007/s10555-012-9412-6
[23] M. Dandri, M. Lütgehetmann and J. Petersen, “Experimental Models and Therapeutic Approaches for HBV,” Seminars in Immunopathology, Vol. 35, No. 1, 2012, pp. 7-21. doi:10.1007/s00281-012-0335-7
[24] S. Preiss, A. Thompson, X. Chen, S. Rodgers, V. Markovska, et al., “Characterization of the Innate Immune Signalling Pathways in Hepatocyte Cell Lines,” Journal of Viral Hepatitis, Vol. 15, No. 12, 2008, pp. 888-900. doi:10.1111/j.1365-2893.2008.01001.x
[25] A. J. Thompson, D. Colledge, S. Rodgers, R. Wilson, P. Revill , et al., “Stimulation of the Interleukin-1 Receptor and Toll-Like Receptor 2 Inhibits Hepatitis B Virus Replication in Hepatoma Cell Lines in Vitro,” Antiviral Therapy, Vol. 14, No. 6, 2009, pp. 797-808.
[26] T. B. Lentz and D. D. Loeb, “Development of Cell Cultures that Express Hepatitis B Virus to High Levels and Accumulate cccDNA,” Journal of Virological Methods, Vol. 169, No. 1, 2010, pp. 52-60. doi:10.1016/j.jviromet.2010.06.015
[27] T. B. Lentz and D. D. Loeb, “Roles of the Envelope Proteins in the Amplification of Covalently Closed Circular DNA and Completion of Synthesis of the Plus-Strand DNA in Hepatitis B Virus,” Journal of Virology, Vol. 85, No. 22, 2011, pp. 11916-11927. doi:10.1128/JVI.05373-11
[28] J. Kock, C. Rosler, J. J. Zhang, H. E. Blum, M. Nassal and C. Thoma, “Generation of Covalently Closed Circular DNA of Hepatitis B Viruses via Intracellular Recycling Is Regulated in a Virus Specific Manner,” PLoS Pathogens, Vol. 6, No. 9, 2010, p. e1001082. doi:10.1371/journal.ppat.1001082
[29] T. Pollicino, L. Belloni, G. Raffa, N. Pediconi, G. Squadrito, et al., “Hepatitis B Virus Replication Is Regulated by the Acetylation Status of Hepatitis B Virus cccDNABound H3 and H4 Histones,” Gastroenterology, Vol. 130, No. 3, 2006, pp. 823-837.
[30] S. Locarnini, T. Shaw, J. Dean, D. Colledge, A. Thompson, et al., “Cellular Response to Conditional Expression of the Hepatitis B Virus Precore and Core Proteins in Cultured Hepatoma (Huh-7) cells,” Journal of Clinical Virology, Vol. 32, No. 2, 2005, pp. 113-121.
[31] X. Zhang, H. Zhang and L. Ye, “Effects of Hepatitis B Virus X Protein on the Development of Liver Cancer,” Journal of Laboratory and Clinical Medicine, Vol. 147, No. 2, 2006, pp. 58-66.
[32] H. C. Wang, W. Huang, M. D. Lai and I. J. Su, “Hepatitis B Virus Pre-S Mutants, Endoplasmic Reticulum Stress and Hepatocarcinogenesis,” Cancer Science, Vol. 97, No. 8, 2006, pp. 683-688. doi:10.1111/j.1349-7006.2006.00235.x
[33] H. Yu, R. Zhu, Y. Z. Zhu, Q. Chen and H. G. Zhu, “Effects of Mutations in the X Gene of Hepatitis B Virus on the Virus Replication,” Acta Virologica, Vol. 56, No. 2, 2012, pp. 101-110. doi:10.4149/av_2012_02_101
[34] A. Le Bon, G. Schiavoni, G. D’Agostino, I. Gresser, F. Belardelli, et al., “Type I Interferons Potently Enhance Humoral Immunity and can Promote Isotype Switching by Stimulating Dendritic Cells in Vivo,” Immunity, Vol. 14, No. 4, 2001, pp. 461-470.
[35] M. Kumar, S. Y. Jung, A. J. Hodgson, C. R. Madden, J. Qin and B. L. Slagle, “Hepatitis B Virus Regulatory HBx Protein Binds to Adaptor Protein IPS-1 and Inhibits the Activation of Beta-Interferon,” Journal of Virology, Vol. 85, No. 2, 2011, pp. 987-995. doi:10.1128/JVI.01825-10
[36] B. Y. Jiao, W. S. Lin, F. F. She, W. N. Chen and X. Lin, “Hepatitis B Virus X Protein Enhances Activation of Nuclear Factor κB through Interaction with Valosin-Containing Protein,” Archives of Virology, Vol. 156, No. 11, 2011, pp. 2015-2021. doi:10.1007/s00705-011-1099-4
[37] R. Tang, F. Kong, L. Hu, H. You, P. Zhang, et al., “Role of Hepatitis B Virus X Protein in Regulating LIM and SH3 Protein 1 (LASP-1) Expression to Mediate Proliferation and Migration of Hepatoma Cells,” Virology Journal, Vol. 16, No. 9, 2012, p. 163. doi:10.1186/1743-422X-9-163
[38] P. Bellecave, J. Gouttenoire, M. Gajer, V. Brass, G. Koutsoudakis, et al., “Hepatitis B and C Virus Coinfection: A Novel Model System Reveals the Absence of Direct Viral Interference,” Hepatology, Vol. 50, No. 1, 2009, pp. 46-55. doi:10.1002/hep.22951
[39] P.-Y. Ke and S. S.-L. Chen, “Hepatitis C Virus and Cellular Stress Response: Implications to Molecular Pathogenesis of Liver Diseases,” Viruses, Vol. 4, No. 10, 2012, pp. 2251-2290. doi:10.3390/v4102251
[40] K. D. Tardif, K. Mori and A. Siddiqui, “Hepatitis C Virus Subgenomic Replicons Induce Endoplasmic Reticulum Stress Activating an Intracellular Signaling Pathway,” Journal Virology, Vol. 76, No. 15, 2002, pp. 7453-7459. doi:10.1128/JVI.76.15.7453-7459.2002
[41] A. von dem Bussche, R. Machida, K. Li, G. Loevinsohn, A. Khander, J. Wang, et al., “Hepatitis C Virus NS2 Protein Triggers Endoplasmic Reticulum Stress and Suppresses its Own Viral leplication,” Journal of Hepatology, Vol. 53, No. 5, 2010, pp. 797-804. doi:10.1016/j.jhep.2010.05.022
[42] S. Li, L. Ye, X. Yu, B. Xu, K. Li, et al., “Hepatitis C Virus NS4B Induces Unfolded Protein Response and Endoplasmic Reticulum Overload Response-Dependent NF-Kappab Activation” Virology, Vol. 391, No. 2, 2009, pp. 257-264.
[43] D. Sir, W. L. Chen, J. Choi, T. Wakita, T. S. Yen and J. H. Ou, “Induction of Incomplete Autophagic Response by Hepatitis C Virus via the Unfolded Protein Response,” Hepatology, Vol. 48, No. 4, 2008, pp. 1054-1061. doi:10.1002/hep.22464
[44] P. Y. Ke and S. S. Chen, “Activation of the Unfolded Protein Response and Autophagy after Hepatitis C Virus Infection Suppresses Innate Antiviral Immunity in Vitro,” Journal of Clinical Investigations, Vol. 121, No. 1, 2011, pp. 37-56. doi:10.1172/JCI41474
[45] S. Taguwa, H. Kambara, N. Fujita, T. Noda, T. Yoshimori, et al., “Dysfunction of Autophagy Participates in Vacuole Formation and Cell Death in Cells Replicating Hepatitis C Virus,” Journal of Virology, Vol. 85, No. 24, 2011, pp. 13185-13194. doi:10.1128/JVI.06099-11
[46] V. C. Chu, S. Bhattacharya, A. Nomoto, J. Lin, S. K. Zaidi, et al., “Persistent Expression of Hepatitis C Virus Non-Structural Proteins Leads to Increased Autophagy and Mitochondrial Injury in Human Hepatoma Cells,” PLoS ONE, Vol. 6, 2011, p. 28551. doi:10.1371/journal.pone.0028551
[47] T. Vescovo, A. Romagnoli, A. B. Perdomo, M. Corazzari, F. Ciccosanti, et al., “Autophagy Protects Cells from HCV-Induced Defects in Lipid Metabolism,” Gastroenterology, Vol. 142, No. 3, 2012, pp. 644-653.
[48] G. C. Das and F. B. Hollinger, “Molecular Pathways for Glucose Homeostasis, Insulin Signaling and Autophagy in Hepatitis C Virus Induced Insulin Resistance in a Cellular Model,” Virology, Vol. 434, No. 1, 2012, pp. 5-17. doi:10.1016/j.virol.2012.07.003
[49] P. Zhao, T. Han, J. J. Guo, S. L. Zhu, J. Wang, et al., “HCV NS4B Induces Apoptosis through the Mitochondrial Death Pathway,” Virus Research, Vol. 169, No. 1, 2012, pp. 1-7. doi:10.1016/j.virusres.2012.04.006
[50] E. A. Prikhod’ko, G. G. Prikhod’ko, R. M. Siegel, P. Thompson, M. E. Major and J. I. Cohen, “The NS3 Protein of Hepatitis C Virus Induces Caspase-8-Mediated Apoptosis Independent of Its Protease or Helicase Activities,” Virology, Vol. 329, No. 1, 2004, pp. 53-67. doi:10.1016/j.virol.2004.08.012
[51] S. H. Lee, Y. K. Kim, C. S. Kim, S. K. Seol, J. Kim, et al., “E2 of Hepatitis C Virus Inhibits Apoptosis,” The Journal of Immunology, Vol. 175, No. 12, 2005, pp. 8226-8235.
[52] M. Tanaka, M. Nagano-Fujii, L. Deng, S. Ishido, et al., “Single-Point Mutations of Hepatitis C Virus NS3 that Impair p53 Interaction and Anti-Apoptotic Activity of NS3,” Biochemical and Biophysical Research Communications, Vol. 340, No. 3, 2006, pp. 792-799. doi:10.1016/j.bbrc.2005.12.076
[53] H. L. Chiou, Y. S. Hsieh, M. R. Hsieh and T. Y. Chen, “HCV E2 May Induce Apoptosis of Huh-7 Cells via a Mitochondrial-Related Caspase Pathway,” Biochemical and Biophysical Research Communications, Vol. 345, No. 1, 2006, pp. 453-458. doi:10.1016/j.bbrc.2006.04.118
[54] Y. Nomura-Takigawa, M. Nagano-Fujii, L. Deng, S. Kitazawa, S. Ishido, et al., “Non-Structural Protein 4A of Hepatitis C Virus Accumulates on Mitochondria and Renders the Cells Prone to Undergoing MitochondriaMediated Apoptosis,” Journal of General Virology, Vol. 87, No. 7, 2006, pp. 1935-1945. doi:10.1099/vir.0.81701-0
[55] H. Zhu, H Dong, E. Eksioglu, A. Hemming, M. Cao, et al., “Hepatitis C Virus Triggers Apoptosis of a Newly Developed Hepatoma Cell Line through Antiviral Defense System,” Gastroenterology, Vol. 133, No. 5, 2007, pp. 1649-1659. doi:10.1053/j.gastro.2007.09.017
[56] K. H. Lan, M. L. Sheu, S. J. Hwang, S. H. Yen, S. Y. Chen, et al., “HCV NS5A Interacts with P53 and Inhibits P53-Mediated Apoptosis,” Oncogene, Vol. 21, No. 31, 2002, pp. 4801-4811. doi:10.1038/sj.onc.1205589
[57] D. G. Johnson and C. L. Walker, “Cyclins and Cell Cycle Checkpoints,” Annual Review of Pharmacology and Toxicology, Vol. 39, No. 1, 1999, pp. 39:295-312.
[58] V. Sanchez and D. H. Spector, “Subversion of Cell Cycle Regulatory Pathways,” Current Topics in Microbiology and Immunology, Vol. 325, 2008, pp. 243-262.
[59] M. Hassan, H. Ghozlan and O. Abdel-Kader, “Activation of RB/E2F Signaling Pathway Is Required for the Modulation of Hepatitis C Virus Core Protein-Induced Cell Growth in Liver and Non-Liver Cells,” Cellular Signalling, Vol. 16, No. 12, 2004, pp. 1375-1385. doi:10.1016/j.cellsig.2004.04.005
[60] T. Munakata, Y. Liang, S. Kim, D. R. McGivern, J. Huibregtse, et al., “Hepatitis C Virus Induces E6AP-Dependent Degradation of the Retinoblastoma Protein,” PLoS Pathogens, Vol. 3, No. 9, 2007, pp. 1335-1347. doi:10.1371/journal.ppat.0030139
[61] D. R. McGivern, R. A. Villanueva, S. Chinnaswamy, C. C. Kao and S. M. Lemon, “Impaired Replication of Hepatitis C Virus Containing Mutations in a Conserved NS5B Retinoblastoma Protein-Binding Motif,” Journal of Virology, Vol. 83, No. 15, 2009, pp. 7422-7433. doi:10.1128/JVI.00262-09
[62] K. Machida, J. C. Liu, G. McNamara, A. Levine, L. Duan and M. M. Lai, “Hepatitis C Virus Causes Uncoupling of Mitotic Checkpoint and Chromosomal Polyploidy through the Rb Pathway,” Journal of Virology, Vol. 83, No. 23, 2009, pp. 12590-12600. doi:10.1128/JVI.02643-08
[63] R. P. Kannan, L. L. Hensley, L. E. Evers, S. M. Lemon and D. R. McGivern, “Hepatitis C Virus Infection Causes Cell Cycle Arrest at the Level of Initiation of Mitosis,” Journal of Virology, Vol. 85, No. 16, 2011, pp. 7989-8001. doi:10.1128/JVI.00280-11
[64] K. Machida, G. McNamara, K. T. Cheng, J. Huang, C. H. Wang, et al., “Hepatitis C Virus Inhibits DNA Damage Repair Through Reactive Oxygen and Nitrogen Species and by Interfering with the ATM-NBS1/-Mre11/ Rad50 DNA Repair Pathway in Monocytes and Hepatocytes,” The Journal of Immunology, Vol. 185, No. 11, 2010, pp. 6985-6998. doi:10.4049/jimmunol.1000618
[65] C. K. Lai, K. S. Jeng, K. Machida, Y. S. Cheng and M. M. Lai, “Hepatitis C Virus NS3/4A Protein Interacts with ATM, Impairs DNA Repair and Enhances Sensitivity to Ionizing Radiation,” Virology, Vol. 370, No. 2, 2008, pp. 295-309.
[66] IARC, “Agents Classified by the IARC Monographs,” 2011. http://monographs.iarc.fr/ENG/Classi fication/ClassificationsGroupOrder.pdf
[67] Q. V. Tu, A. S. Okoli, Z. Kovach and G. L. Mendz, “Hepatocellular Carcinoma: Prevalence and Molecular Pathogenesis of Helicobacter spp,” Future Microbiology, Vol. 4, No. 10, 2009, pp. 1283-1301. doi:10.2217/fmb.09.90
[68] P. Avenaud, B. Le Bail, K. Mayo, A. Marais, R. Fawaz, et al., “Natural History of Helicobacter hepaticus Infection in Conventional A/J mice, with Special Reference to Liver Involvement,” Infection and Immunity, Vol. 71, No. 6, 2003, pp. 3667-3672. doi:10.1128/IAI.71.6.3667-3672.2003
[69] E. Le Roux-Goglin, C. Varon, P. Spuul, C. Asencio, F. Megraud, et al., “Helicobacter Infection Induces Podosome Assembly in Primary Hepatocytes in Vitro,” European Journal of Cell Biology, Vol. 91, No. 3, 2012, pp. 161-170. doi:10.1016/j.ejcb.2011.11.003
[70] S. Linder and M. Aepfelbacher, “Podosomes: Adhesion Hot-Spots of Invasive Cells,” Trends in Cell Biology, Vol. 13, No. 7, 2003, pp. 376-385. doi:10.1016/S0962-8924(03)00128-4
[71] W. B. VanWinkle, M. Snuggs and L. M. Buja, “Hypoxiainduced Alterations in Cytoskeleton Coincide with Collagenase Expression in Cultured Neonatal Rat Cardiomyocytes,” Journal of Molecular and Cellular Cardiology, Vol. 27, No. 12, 1995, pp. 2531-2542. doi:10.1006/jmcc.1995.0040
[72] A. S. Okoli, M. J. Raftery and G. L. Mendz, “Comparison of Helicobacter bilis—Associated Protein Expression in Huh7 Cells Harbouring HCV Replicon and in RepliconCured Cells,” International Journal of Hepatology, Vol. 12, 2012, pp. 501-671.
[73] A. S. Okoli, “Molecular Studies of the Response of Helicobacter hepaticus to Bile, and the Effect of Helicobacter bilis on Human Hepatoma Cells,” PhD Thesis, University of New South Wales, Sydney, 2009.
[74] Y. Nishimura-Sakurai, N. Sakamoto, K. Mogushi, S. Nagaie, M. Nakagawa, et al., “Comparison of HCV-associated Gene Expression and Cell Signaling Pathways in Cells with or without HCV Replicon and in RepliconCured Cells,” Journal of Gastroenterology, Vol. 45, No. 5, 2010, pp. 523-536.
[75] E. Genoux, E. Nicolle and A. Boumendjel, “Flavonoids as Anticancer Agents: Recent Progress and State of the Art?” Current Organic Chemistry, Vol. 15, No. 15, 2011, pp. 2608-2615.
[76] B. R. Kim, Y. K. Jeon and M. J. Nam, “A Mechanism of Apigenin-Induced Apoptosis is Potentially Related to Anti-Angiogenesis and Anti-Migration in Human Hepatocellular Carcinoma Cells,” Food and Chemical Toxicology, Vol. 49, No. 7, 2011, pp. 1626-1632. doi:10.1016/j.fct.2011.04.015
[77] H. Moinova, “Aberrant Vimentin Methylation Is Characteristic of Upper GI Pathologies,” Cancer Epidemiology Biomarkers & Prevention, Vol. 21, No. 4, 2012, pp. 594-600. doi:10.1158/1055-9965.EPI-11-1060
[78] W. Jeon, Y. K. Heon and M. J. Nam, “Apoptosis by Aloe-Emodin Is Mediated through Down-Regulation of Calpain-2 and Ubiquitin-Protein Ligase E3A in Human Hepatoma Huh-7 Cells,” Cell Biology International, Vol. 36, No. 2, 2012, pp. 163-167. doi:10.1042/CBI20100723
[79] D. R. Yoo, Y. H. Jang, Y. K. Jeon, J. Y. Kim, W, Jeon, et al., “Proteomic Identification of Anti-Cancer Proteins in Luteolin-Treated Human Hepatoma Huh-7 Cells,” Cancer Letters, Vol. 282, No. 1, 2009, pp. 48-54. doi:10.1016/j.canlet.2009.02.051
[80] J. Y. Kim, Y. K. Jeon, W. Jeon and M. J. Nam, “Fisetin Induces Apoptosis in Huh-7 Cells via Downregulation of BIRC8 and Bcl2L2,” Food and Chemical Toxicology, Vol. 48, No. 8-9, 2010, pp. 2259-2264. doi:10.1016/j.fct.2010.05.058
[81] T. A. Mansoor, R. M. Ramalho, X. Luo, C. Ramalhete, C. M. P. Rodrigues and M. J. U. Ferreira, “Isoflavones as Apoptosis Inducers in Human Hepatoma HuH-7 Cells,” Physiotherapy Research, Vol. 25, No. 12, 2011, pp. 1819-1824. doi:10.1002/ptr.3498
[82] S. Hong, K. H. Jung, H. Lee, M. Choi, H. Zheng, M. K. Son, G. Lee and S. Hong, “Apoptotic and Anti-Angiogenic Effects of Pulsatilla koreana Extract on Hepatocellular Carcinoma,” Internal Journal of Oncology, Vol. 40, No. 2, 2011, pp. 452-460. doi:10.3892/ijo.2011.1204
[83] C-C. Lee, Y-H. Lin, W-H. Chang, P-C. Lin, Y-C. Wu and J-G. Chang, “Squamocin Modulates Histone H3 Phosphorylation Levels and Induces G1 Phase Arrest and Apoptosis in Cancer Cells,” BMC Cancer, Vol. 11, No. 58, 2011. doi:10.1186/1471-2407-11-58
[84] P. C. Liao, L. T. Ng, L. T. Lin, C. D. Richardson, G. H. Wang and C. C. Lin, “Resveratrol Arrests Cell Cycle and Induces Apoptosis in Human Hepatocellular Carcinoma Huh-7 Cells,” Journal of Medicinal Food, Vol. 13, No. 6, 2010, pp. 1415-1423. doi:10.1089/jmf.2010.1126
[85] T. A. Mansoor, R. M. Ramalho, S. Mulhovo, C. M. Rodrigues and M. J. Ferreira, “Induction of Apoptosis in Huh-7 Cancer Cells by Monoterpene and Beta-Carboline Indole Alkaloids Isolated from the Leaves of Tabernaemontana elegans,” Bioorganic & Medicinal Chemistry Letters, Vol. 19, No. 15, 2009, pp. 4255-4258. doi:10.1016/j.bmcl.2009.05.104
[86] Q. F. Wang, J. C. Chen, S. J. Hsieh, C. C. Cheng and S. L. Hsiu, “Regulation of Bcl-2 family molecules and Activation of Caspase Cascade Involved in GypenosidesInduced Apoptosis in Human Hepatoma Cells,” Cancer Letters, Vol. 183, No. 2, 2002, pp. 169-178. doi:10.1016/S0304-3835(01)00828-X
[87] Q. F. Wang, C. W. Chiang, C. C. Wu, C. C. Cheng, S. J. Hsieh, et al., “Gypenosides Induce Apoptosis in Human Hepatoma Huh-7 Cells through a Calcium/Reactive Oxygen Species-Dependent Mitochondrial Pathway,” Planta Medica, Vol. 73, No. 6, 2007, pp. 535-544. doi:10.1055/s-2007-967200
[88] J. Y. Lee, K. H. Jung, M. J. Morgan, Y. R. Kang and H. S. Lee, et al., “Sensitization of TRAIL-Induced Cell Death by 20S-Ginsenoside Rg3 via CHOP-Mediated DR5 UpRegulation in Human Hepatocellular Carcinoma Cells,” Molecular Cancer Therapeutics, 10 October 2012.
[89] S. Baig and M. Alamgir, “Cell Death Induced by Morarah and Khaltita in Hepatoma Cancer Cells (Huh-7),” Journal of the College of Physicians and Surgeons Pakistan, Vol. 19, No. 10, 2009, pp. 644-648.
[90] J. Hou, D. Wang, R. Zhang and H. Wang, “Experimental Therapy of Hepatoma with Artemisinin and its Derivatives: In Vitro and in Vivo Activity, Chemosensitization, and Mechanisms of Action,” Clinical Cancer Research, Vol. 14, No. 17, 2007, pp. 5519-5530.
[91] D. Davar, J. H. Beumer, L. Hamieh and H. Tawbi, “Role of PARP Inhibitors in Cancer Biology and Therapy,” Current Medicinal Chemistry, Vol. 19, No. 23, 2012, pp. 3907-3921. doi:10.2174/092986712802002464
[92] M. H. Shu, T. C. Ko and G. C. Yen, “Oleanoic Acid and Ursolic Acid Induce Apoptosis in Huh-7 Human Hepatocellular Carcinoma Cells through a Mitochondrial-Dependent Pathway and Down-Regulation of XIAP,” Journal of Agricultural and Food Chemistry, Vol. 58, No. 10, 2010, pp. 6110-6118. doi:10.1021/jf100574j
[93] Y. Shidoji and H. Ogawa. “Natural Occurrence of CancerPreventive Geranyl-Geranoic Acid in Medicinal Herbs,” Journal of Lipid Research, Vol. 45, No. 6, 2004, pp. 1092-1103. doi:10.1194/jlr.M300502-JLR200
[94] K. Okamoto, Y. Sakimoto, K. Imai, H. Senoo and Y. Shidoji, “Induction of an Incomplete Autophagic Response by Cancer-Preventive Geranlygeranoic Acid in a Human Hepatoma-Derived Cell Line,” Biochemical Journal, Vol. 440, No. 1, 2011, pp. 63-71. doi:10.1042/BJ20110610
[95] S. Shimonishi, T. Muraguchi, M. Mitake, C. Sakane, K. Okamoto and Y. Shidoji, “Rapid Downregulation of Cyclin D1 Induced by Geranylgeranoic Acid in Human Hepatoma Cells,” Nutrition and Cancer, Vol. 64, No. 3, 2012, pp. 473-480.
[96] F. Yamaguchi, M. Takata, K. Kamitori, M. Nonaka, Y. Dong, et al., “Rare Sugar D-Allose Induces Specific UpRegulation of TXNIP and Subsequent G1 Cell Cycle Arrest in Hepatocellular Carcinoma Cells by Stabilization of P27kip1,” International Journal of Oncology, Vol. 32, No. 2, 2008, pp. 377-385.
[97] T. Wu, “Cyclooxygenase-2 in Hepatocellular Carcinoma,” Cancer Treatment Reviews, Vol. 32, No. 1, 2006, pp. 28-44. doi:10.1016/j.ctrv.2005.10.004
[98] S. C. Larsoo, M. Kumlin, M. Ingelman-Sundberg and A. Wolk, “Dietary Long-chain n-3 Fatty Acids for the Prevention of Cancer: A Review of Potential Mechanisms,” American Journal of Clinical Nutrition, Vol. 79, No. 6, 2004, pp. 935-945.
[99] K. Lim, C. Han, Y. Dai, M. Shen and T. Wu, “Omega-3 Polyunsaturated Fatty Acids Inhibit Hepatocellular Carcinoma Cell Growth through Blocking Beta-Catenin and Cyclooxygenase-2,” Molecular Cancer Therapeutics, Vol. 8, No. 11, 2009, pp. 3046-3055. doi:10.1158/1535-7163.MCT-09-0551
[100] T. Yamazaki and T. Tokiwa, “Isofraxidin, a Coumarin Component from Acanthopanax senticosus, Inhibits Matrix Metalloproteinase-7 Expression and Cell Invasion of Human Hepatoma Cells,” Biological and Pharmaceutical Bulletin, Vol. 33, No. 10, 2010, pp. 1716-1722.
[101] F. Rodier and J Campisi, “Four Faces of Cellular Senescence,” The Journal of Cell Biology, Vol. 192, No. 4, 2011, pp. 547-556. doi:10.1083/jcb.201009094
[102] G. S. Oh, H. O. Pae, H. Oh, S. G Hong, I. K. Kim, K. Y. Chai, Y. G. Yun, T. O. Kwon and H. T. Chung. “In vitro Anti-proliferative Effect of 1,2,3,4,6-Penta-O-galloylbeta-D-glucose on Human Hepatocellular Carcinoma Cell Line, SK-HEP-1 Cells,” Cancer Letters, Vol. 174, No. 1, 2001, pp. 17-24. doi:10.1016/S0304-3835(01)00680-2
[103] J. E. Huh, E. O. Lee, M. S. Kim, K. S. Kang, C. H. Kim, et al., “Penta-O-galloyl-b-D-glucose Suppresses Tumor Growth via Inhibition of Angiogenesis and Stimulation of Apoptosis: Roles of Cyclooxygenase-2 and Mitogen-Activated Protein Kinase Pathways,” Carcinogenesis, Vol. 26, No. 8, 2005, pp. 1436-1445. doi:10.1093/carcin/bgi097
[104] S. Yin, Y. Dong, J. Li, J. Lü and H Hu. “Penta-1,2,3,4,6-O-galloyl-beta-D-glucose Induces Senescence-Like Terminal S-Phase Arrest in Human Hepatoma and Breast Cancer Cells,” Molecular Carcinogenesis, Vol. 50, No. 8, 2011, pp. 592-600. doi:10.1002/mc.20743
[105] A. X. Zhu, “Systemic Therapy of Advanced Hepatocellular Carcinoma: How Hopeful Should We Be?” The Oncologist, Vol. 11, No. 7, 2006, pp. 790-800. doi:10.1634/theoncologist.11-7-790
[106] M. B. Thomas, “Systemic Therapy for Hepatocellular Carcinoma,” Cancer Journal, Vol. 14, No. 2, 2008, pp. 123-127. doi:10.1097/PPO.0b013e31816a6058
[107] F. van Zijl, G. Zulehner, M. Petz, D. Schneller and D. C. Kornauth, et al., “Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma,” Future Oncology, Vol. 5, No. 8, 2009, pp. 1169-1179. doi:10.2217/fon.09.91
[108] Q. D. Hu, W. Chen, T. L Yan, T. Ma, C. L. Chen, et al., “NSC 74859 Enhances Doxorubicin Cytotoxicity via Inhibition of Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma Cells,” Cancer Letters, Vol. 325, No. 2, 2012, pp. 207-213. doi:10.1016/j.canlet.2012.07.003
[109] T. Reya, S. J. Morrison, M. F. Clarke and I. L. Weissman, “Stem Cells, Cancer, and Cancer Stem Cells,” Nature, Vol. 414, No. 1, 2001, pp. 105-111. doi:10.1038/35102167
[110] S. J. Myung, J. H. Yoon and S. J Yu, “STAT3 & Cytochrome P450 2C9: A Novel Signaling Pathway in Liver Cancer Stem Cells,” Biomedicine & Pharmacotherapy, Vol. 66, No. 8, 2012, pp. 612-616. doi:10.1016/j.biopha.2012.08.011
[111] T. Zheng, J. Wang, X. Song, X. Meng, S. Pan, H. Jiang and L. Liu, “Nutlin-3 Cooperates with Doxorubicin to Induce Apoptosis of Human Hepatocellular Carcinoma Cells through P53 or P73 Signaling Pathways,” Journal of Cancer Research and Clinical Oncology, Vol. 136, No. 10, 2010, pp. 1597-1604. doi:10.1007/s00432-010-0817-8
[112] Y. Kawano, M. Nagata, T. Kohno, A. Ichimiya, T. Iwakiri, M. Okumura and K. Arimori, “Caffeine Increases the Antitumor Effect of Cisplatin in Human Hepatocellular Carcinoma Cells,” Biological and Pharmaceutical Bulletin, Vol. 35, No. 3, 2012, pp. 400-407. doi:10.1248/bpb.35.400
[113] S. Hyuga, M. Shiraishi, A. Hori, M. Hyuga and T. Hanawa, “Effects of Kampo Medicines on MDR-1-Mediated Multidrug Resistance in Human Hepatocellular Carcinoma Huh-7/PTX Cells,” Biological and Pharmaceutical Bulletin, Vol. 35, No. 10, 2012, pp. 1729-1739. doi:10.1248/bpb.b12-00371
[114] P. Liu, H. Yu, Y. Sun, M. Zhu and Y. Duan, “A mPEGPLGA-b-PLL Copolymer Carrier for Adriamycin and siRNA delivery,” Biomaterials, Vol. 33, No. 17, 2012, pp. 4403-4412. doi:10.1016/j.bioma terials.2012.02.041
[115] X. Zhang, S. Guo, R. Fan, M. Yu, F. Li, et al., “DualFunctional Liposome for Tumor Targeting and Overcoming Multidrug Resistance in Hepatocellular Carcinoma Cells,” Biomaterials, Vol. 33, No. 29, 2012, pp. 7103-7114. doi:10.1016/j.biomaterials.2012.06.048
[116] J. Guegan, F. Ezan, N. Theret, S. Langouet and G. Baffet, “MAPK Signaling in Cisplatin-Induced Death: Predominant Role of ERK1 over ERK2 in Human Hepatocellular Carcinoma Cells,” Carcinogenesis, Vol. 34, No. 1, 2013, pp. 38-47.
[117] Y. L. Lee, Y. J. Lee, S. J. Ahn, T. H. Choi, B. S. Moon, et al., “Combined Radionuclide-Chemotherapy and in Vivo Imaging of Hepatocellular Carcinoma Cells after Transfection of a Triple-Gene Contruct, NIS, HSV1sr39tk, and EGFP,” Cancer Letters, Vol. 290, No. 1, 2010, pp. 129-138. doi:10.1016/j.canlet.2009.09.004
[118] N. Mendez-Sanchez, F. Vasquez-Fernandez, D. ZamoraValdes and M. Uribe, “Sorafenib, a Systemic Therapy for Hepatocellular Carcinoma,” Annals of Hepatology, Vol. 7, No. 1, 2008, pp. 46-51.
[119] M. B. Thomas and J. L. Abbruzzese, “Opportunities for Targeted Therapies in Hepatocellular Carcinoma,” Journal of Clinical Oncology, Vol. 23, No. 31, 2005, pp. 8093-8108. doi:10.1200/JCO.2004.00.1537
[120] S. Chan and W. Yeo, “Targeted Therapy of Hepatocellular Carcinoma: Present and Future,” Journal of Gastroenterology and Hepatology, Vol. 27, No. 5, 2012, pp. 862-872. doi:10.1111/j.1440-1746.2012.07096.x
[121] NCI, “Drug Directory 2012,” National Cancer Institute, December 2012. http://www.cancer.gov/ drugdi ctionary?cdrid=299013
[122] C. Frenette and R. Gish, “Targeted Systemic Therapies for Hepatocellular Carcinoma: Clinical Perspectives, Challenges and Implications,” World Journal of Gastroenterology, Vol. 18, No. 6. 2012, pp. 498-506. doi:10.3748/wjg.v18.i6.498
[123] W. T. Tai, A. L. Cheng, C. W. Shiau, H. P. Huang, J. W. Huang, et al., “Signal Transducer and Activator of Transcription 3 Is a Major Kinase-Independent Target of Sorafenib in Hepatocellular Carcinoma,” Journal of Hepatology, Vol. 55, No. 5, 2011, pp. 1041-1048. doi:10.1016/j.jhep.2011.01.047
[124] K. F. Chen, C. W. Shiau, C. Y. Liu, P. Y. Chu, W. T. Tai, et al., “Sorafenib and Its Derivative SC-49 Sensitize Hepatocellular Carcinoma Cells to CS-1008, a Humanized Anti-DR5 Antibody,” British Journal of Pharmacology, Vol. 168, No. 3, 2013, pp. 658-672. doi:10.1111/j.1476-5381.2012.02212.x
[125] D. L. Ou, Y. C. Shen, J. D. Liang, J. Y. Liou, S. L. Yu, et al., “Induction of Bim Expression Contributes to the Antitumor Synergy between Sorafenib and MitogenActivated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase Inhibitor CI-1040 in Hepatocellular Carcinoma,” Clinical Cancer Research, Vol. 15, No. 18, 2009, pp. 5820-5828. doi:10.1158/1078-0432.CCR-08-3294
[126] R. W. Johnstone, A. J. Frew and M. J. Smyth, “The TRAIL Apoptotic Pathway in Cancer Onset, Progression and Therapy,” Nature Reviews Cancer, Vol. 8, No. 10, 2008, pp. 782-798. doi:10.1038/nrc2465
[127] K. F. Chen, W. T. Tai, T. H. Liu, H. P. Huang, Y. C. Lin, et al., “Sorafenib Overcomes TRAIL Resistance of Hepatocellular Carcinoma Cells through the Inhibition of STAT3,” Clinical Cancer Research, Vol. 16, No. 21, 2010, pp. 5189-5199. doi:10.1158/1078-0432.CCR-09-3389
[128] W. T. Tai, A. L. Cheng, C. W. Shiau, C. Y. Liu, C. H. Ko, et al., “Dovitinib Induces Apoptosis and Overcomes Sorafenib Resistance in Hepatocellular Carcinoma through SHP-1: Mediated Inhibition of STAT3,” Molecular Cancer Therapeutics, Vol. 11, No. 2, 2012, pp. 452-463. doi:10.1158/1535-7163.MCT-11-0412
[129] K. F. Chen, H. L. Chen, C. Y. Liu, W. T. Tai, K. Ichikawa, et al., “Dovitinib Sensitizes Hepatocellular Carcinoma Cells to TRAIL and Tigatuzumab, a Novel Anti-DR5 Antibody, through SHP-1-Dependent Inhibition of STAT3,” Biochemical Pharmacology, Vol. 83, No. 6, 2012, pp. 769-777. doi:10.1016/j.bcp.2011.12.035
[130] B. Fleischer, H. Schulze-Bergkamen, M. Schuchmann, A. Weber, S. Biesterfeld, et al., “Mcl-1 Is an AntiApoptotic Factor for Human Hepatocellular Carcinoma,” International Journal of Oncology, Vol. 28, No. 1, 2006, pp. 25-32.
[131] K. F. Chen, J. C. Su, C. Y. Liu, J. W. Huang, K. C. Chen, W. L. Chen, W. T. Tai and C. W. Shiau, “A Novel Obatoclax Derivative, SC-2001, Induces Apoptosis in Hepatocellular Carcinoma Cells through SHP-1-Dependent STAT3 Inactivation,” Cancer Letters, Vol. 321, No. 1, 2012, pp. 27-35. doi:10.1016/j.canlet.2012.03.023
[132] J. H. Lee, H. Lee, S. M. Yun, K. H. Jung, Y. Jeong, et al., “IPD-196, a Novel Phosphatidylinositol 3-Kinase Inhibitor with Potent Anticancer Activity against Hepatocellular Carcinoma,” Cancer Letters, Vol. 322, No. 1, 2013. pp. 99-108.
[133] K. H. Jung, H. M. Zheng, Y. Jeong, M. J. Choi, H. Lee, S.W. Hong, H. S. Lee, M. K. Son, S. Lee, S. Hong and S. S. Hong, “Suppression of Tumor Proliferation and Angiogenesis of Hepatocellular Carcinoma by HS-104, a Novel Phosphoinositide 3-Kinase Inhibitor,” Cancer Letters, Vol. 328, No. 1, 2013, pp. 176-187. doi:10.1016/j.canlet.2012.08.005
[134] K. H. Jung, M. J. Choi, S. Hong, H. Lee, S. W. Hong, H. M. Zheng, H. S. Lee, S. Hong and S. S. Hong, “HS-116, a Novel Phosphatidylinositol 3-Kinase Inhibitor Induces Apoptosis and Suppresses Angiogenesis of Hepatocellular Carcinoma Through Inhibition of the PI3K/AKT/mTOR Pathway,” Cancer Letters, Vol. 316, No. 2, 2011, pp. 187-195. doi:10.1016/j.canlet.2011.10.037
[135] K. F. Chen, P. Y. Yeh, K. H. Yeh, Y. S. Lu, S. Y. Huang and A. L. Cheng, “Down-Regulation of Phospho-Akt Is a Major Molecular Determinant of Bortezomib-Induced Apoptosis in Hepatocellular Carcinoma Cells,” Cancer Research, Vol. 68, No. 16, 2008, pp. 6698-6707. doi:10.1158/0008-5472.CAN-08-0257
[136] K. F. Chen, P. Y. Yeh, C. Hsu, C. H. Hsu, Y. S. Lu, et al., “Bortezomib Overcomes Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Resistance in Hepatocellular Carcinoma Cells in Part through the Inhibition of the Phosphatidylinositol 3-Kinase/Akt Pathway,” Journal of Biological Chemistry, Vol. 284, No. 17, 2009, pp. 11121-11133. doi:10.1074/jbc.M806268200
[137] K. F. Chen, H. C. Yu, T. H. Liu, S. S. Lee, P. J. Chen and A. L. Cheng, “Synergistic Interactions between Sorafenib and Bortezomib in Hepatocellular Carcinoma Involve PP2A-Dependent Akt Inactivation,” Journal of Hepatology, Vol. 52, No. 1, 2009, pp. 88-95. doi:10.1016/j.jhep.2009.10.011
[138] T. R. Peterson, M. Laplante, C. C. Thoreen, Y. Sancak, S. A. Kang, et al., “DEPTOR Is an mTOR Inhibitor Frequently Overexpressed in Multiple Myeloma Cells and Required for Their Survival,” Cell, Vol. 137, No. 5, 2009, pp. 873-886. doi:10.1016/j.cell.2009.03.046
[139] C. H. Yen, Y. C. Lu, C. H. Li, C. M. Lee, C. Y. Chen, et al., “Functional Characterization of Glycine N-Methyl-Transferase and Its Interactive Protein DEPDC6/-DEPTOR in Hepatocellular Carcinoma,” Molecular Medicine, Vol. 18, No. 1, 2012, pp. 286-296. doi:10.2119/molmed.2011.00331
[140] M. H. Chien, T. H. Ying, S. F. Yang, J. K. Yu, C. W. Hsu, S. C. Hsieh and Y. H. Hsieh, “Lipocalin-2 Induces Apoptosis in Human Hepatocellular Carcinoma Cells through Activation of Mitochondria Pathways,” Cell Biochemistry and Biophysics, Vol. 63, No. 3, 2012, pp. 177-186. doi:10.1007/s12013-012-9370-1
[141] H. Yang, N. Bushue, P. Bu and Y. J. Wan, “Induction and Intracellular Localization of Nur77 Dictate FenretinideInduced Apoptosis of Human Liver Cancer Cells,” Biochemical Pharmacology, Vol. 79, No. 7, 2009, pp. 948-954. doi:10.1016/j.bcp.2009.11.004
[142] P. U. Emeagi, K. Thielemans and K. Breckpot, “The Role of SMAC Mimetics in Regulation of Tumor Cell Death and Immunity,” OncoImmunology, Vol. 1, No. 6, 2012, pp. 965-967. doi:10.4161/onci.20369
[143] K. Chen, J. Lin, C. Shiau, W. Tai, C. Liu, H. Yu, P. Chen and A. Cheng, “Inhibition of Bcl-2 Improves Effect of LCL161, a SMAC Mimetic, in Hepatocellular Carcinoma Cells,” Biochemical Pharmacology, Vol. 84, No. 3, 2012, pp. 268-277. doi:10.1016/j.bcp.2012.04.023
[144] S. W. Hong, K. H. Jung, H. S. Lee, M. J. Choi, M. K. Son, H. M. Zheng and S. S. Hong, “SB365 Inhibits Angiogenesis and Induces Apoptosis of Hepatocellular Carcinoma through Modulation of PI3K/Akt/mTOR Signaling Pathway,” Cancer Science, Vol. 103, No. 11, 2012, pp. 1929-1937. doi:10.1111/j.1349-7006.2012.02409.x
[145] R. Hrabakova, M. Kollareddy, J. Tyleckova, P. Halada, M. Hajduch, S. J. Gadher and H. Kovarova, “Cancer Cell Resistance to Aurora Kinase Inhibitors: Identification of Novel Targets for Cancer Therapy,” Journal of Proteome Research, Vol. 12, No. 1, 2012, pp. 455-469. doi:10.1021/pr300819m
[146] D. Benten, G. Keller, A. Quaas, J. Schrader, A. Gontarewicz, S. Balabanov, M. Braig, H. Wege, J. Moll, A. W. Lohse and T. H. Brummendorf, “Aurora Kinase Inhibitor PHA-739358 Suppresses Growth of Hepatocellular Carcinoma in Vitro and in a Xenograft Mouse Model,” Neoplasia, Vol. 11, No. 9, 2009, pp. 934-944.
[147] S. Kummar and N. Q. Shafi, “Metastatic Hepatocellular Carcinoma,” Clinical Oncology, Vol. 15, No. 5, 2003, pp. 288-294. doi:10.1016/S0936-6555(03)00067-0
[148] F. van Roy and G. Berx, “The Cell-Cell Adhesion Molecule E-Cadherin,” Cellular and Molecular Life Sciences, Vol. 65, No. 23, 2008, pp. 3756-3788. doi:10.1007/s00018-008-8281-1
[149] T. Nagai, T. Arao, K. Faruta, K. Sakai, K. Kudo, et al., “Sorafenib Inhibits the Hepatocyte Growth Factor-Mediated Epithelial Mesenchymal Transition in Hepatocellular Carcinoma,” Molecular Cancer Therapeutics, Vol. 10, No. 1, 2011, pp. 169-177. doi:10.1158/1535-7163.MCT-10-0544
[150] H. Hao, J. Liu, G. Liu, D. Guan, Y. Yang, X. Zhang, X. Cao and Q. Liu, “Depletion of GRIM-19 Accelerates Hepatocellular Carcinoma Invasion via Inducing EMT and Loss of Contact Inhibition,” Journal of Cellular Physiology, Vol. 227, No. 3, 2012, pp. 1212-1219. doi:10.1002/jcp.24025
[151] V. Esposito, A. Verdina, L. Manente, E. P. Spugnini, R. Vigietti, et al., “Amprenavir Inhibits the Migration in Human Hepatocarcinoma Cell in Vitro and the Growth Xenografts in Vivo,” Journal of Cellular Physiology, Vol. 228, No. 3, 2013, pp. 640-645. doi:10.1002/jcp.24173
[152] M. A. Hawkins and L. A. Dawson, “Radiation Therapy for Hepatocellular Carcinoma: From Palliation to Cure,” Cancer, Vol. 106, No. 8, 2006, pp. 1653-1663. doi:10.1002/cncr.21811
[153] M. E. Perry, “Mdm2 in the Response to Radiation,” Molecular Cancer Research, Vol. 2, No. 1, 2004, pp. 9-19.
[154] W. S. Koom, S. Y. Park, W. Kim, M. Kim, J. S. Kim, H. Kim, I. K. Choi, C. O. Yun and J. Seong, “Combination of Radiotherapy and Adenovirus-Mediated P53 Gene Therapy for MDM2-Overexpressing Hepatocellular Carcinoma,” Journal of Radiation Research, Vol. 53, No. 2, 2012, pp. 202-210.
[155] Y. S. Lu, C. H. Chou, K. Y. Tzen, M. Gao, A. L. Cheng, S. K. Kulp and J. C. Cheng, “Radiosensitizing Effect of a Phenylbutyrate-Derived Histone Deacetylase Inhibitor in Hepatocellular Carcinoma,” International Journal of Randiation Oncology, Vol. 83, No. 2, 2012, pp. 181-189. doi:10.1016/j.ijrobp.2011.12.022
[156] X. Y. Liu, “Targeting Gene-Virotherapy of Cancer and Its Prosperity,” Cell Research, Vol. 16, 2006, pp. 879-886. doi:10.1038/sj.cr.7310108
[157] A. A. A. M. Danen-Van Oorschot, D. F. Fischer, J. M. Grimbergen, B. Klein, S.-M. Zhang, et al., “Apoptin Induces Apoptosis in Human Transformed and Malignant Cells But Not in Normal Cells,” Proceedings of the National Academy of Science of the United States of America, Vol. 94, No. 11, 1997, pp. 5843-5847. doi:10.1073/pnas.94.11.5843
[158] K. J. Zhang, J. Qian, S.B. Wang and Y. Yang, “Targeting Gene-Viro-Therapy with AFP Driving Apoptin Gene Shows Potent Antitumor Effect in Hepatocarcinoma,” Journal of Biomedical Science, Vol. 19, 2012, p. 20. doi:10.1186/1423-0127-19-20
[159] K. J. Zhang, J. Zhang, Y. M. Wu, J. Qian, X. J. Liu, et al., “Complete Eradication of Hepatomas Using an Oncolytic Adenovirus Containing AFP Promoter Controlling E1A and an E1B Deletion to Drive IL-24 Expression,” Cancer Gene Therapy, Vol 19, No. 9, 2012, pp. 619-629. doi:10.1038/cgt.2012.40
[160] W. C. Tsai, S. D. Hsu, C. S. Hsu, T. C. Lai, S. J. Chen, et al., “MicroRNA-122 Plays a Critical Role in Liver Homeostasis and Hepatocarcinogenesis,” Journal of Clinical Investigations, Vol. 122, No. 8, 2012, pp. 2884-2897. doi:10.1172/JCI63455
[161] S. Bai, M. W. Nasser, B. Wang, S. H. Hsu, J. Datta, et al., “MicroRNA-122 Inhibits Tumorigenic Properties of Hepatocellular Carcinoma Cells and Sensitizes These Cells to Sorafenib,” The Journal of Biological Chemistry, Vol. 284, No. 46, 2009, pp. 32015-32027. doi:10.1074/jbc.M109.016774
[162] R. N. Aravalli, J. Choi, S. Mori, D. Mehra, J. Dong, et al., “Spectroscopic and Calorimetric Evaluation of Chemically Induced Protein Denaturation in HuH-7 Liver cancer Cells and Impact on Cell Survival,” Technology in Cancer Research and Treatment, Vol. 11, No. 5, 2012, pp. 409-527. doi:10.7785/tcrt.2012.500271
[163] S. V. Sharma, D. A. Haber and J. Settleman, “Cell LineBased Platforms to Evaluate the Therapeutic Efficacy of Candidate Anticancer Agents,” Nature Reviews Cancer, Vol. 10, No. 4, 2010, pp. 241-253. doi:10.1038/nrc2820

  
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