Role of Sex Hormones in the Development and Progression of Hepatitis B Virus-Associated Hepatocellular Carcinoma

International Journal of Endocrinology

Volumn 2015, Issue , 2015, Pages

  Montella, Maurizio ^a   D'Arena, Giovanni ^b   Crispo, Anna ^a   Capunzo, Mario ^c   Nocerino, Flavia ^a   Grimaldi, Maria ^a   Barbieri, Antonio ^a   D'Ursi, Anna Maria ^c   Tecce, Mario Felice ^c   Amore, Alfonso ^a   Galdiero, Massimiliano ^d   Ciliberto, Gennaro ^a   Giudice, Aldo ^a  

^a NATIONAL CANCER INSTITUTE   (Italy)

^b REFERRAL CANCER CENTER OF BASILICATA   (Italy)

^c UNIVERSITY OF SALERNO   (Italy)

^d UNIVERSITY OF NAPLES FEDERICO II   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ANDROGEN; ANDROGEN RECEPTOR; CYTOKINE; ESTROGEN; MICRORNA; SEX HORMONE;

CANCER GROWTH; CANCER RISK; DISEASE ASSOCIATION; GENE EXPRESSION; HEPATITIS B; HEPATITIS B VIRUS; HUMAN; LIVER CARCINOGENESIS; LIVER CELL CARCINOMA; MOLECULAR MECHANICS; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SEX DIFFERENCE; UPREGULATION;

EID: 84944251609     PISSN: 16878337     EISSN: 16878345     Source Type: Journal    
DOI: 10.1155/2015/854530     Document Type: Review

References (95)

1. M. Montella, A. Crispo, and A. Giudice,"HCC, diet and metabolic factors: diet and HCC"HepatitisMonthly, vol. 11, no. 3, pp. 159-162, 2011
2. J. M. Llovet, A. Burroughs, and J. Bruix,"Hepatocellular carcinoma"The Lancet, vol. 362, no. 9399, pp. 1907-1917, 2003
3. M. C. Yu, J.-M. Yuan, S. Govindarajan, and R. K. Ross,"Epidemiology of hepatocellular carcinoma"Canadian Journal of Gastroenterology, vol. 14, no. 8, pp. 703-709, 2000
4. L. Gramantieri, F. Fornari, E. Callegari et al. ,"MicroRNA involvement in hepatocellular carcinoma"Journal of Cellular and Molecular Medicine, vol. 12, no. 6A, pp. 2189-2204, 2008
5. H. B. El-Serag and K. L. Rudolph,"Hepatocellular carcinoma: epidemiology and molecular carcinogenesis"Gastroenterology, vol. 132, no. 7, pp. 2557-2576, 2007
6. W.-L. Ma, H.-C. Lai, S. Yeh, X. Cai, and C. Chang,"Androgen receptor roles in hepatocellular carcinoma, fatty liver, cirrhosis and hepatitis"Endocrine-Related Cancer, vol. 21, no. 3, pp. R165-R182, 2014
7. D. M. Parkin,"Global cancer statistics in the year 2000"The Lancet Oncology, vol. 2, no. 9, pp. 533-543, 2001
8. Y.-J. Jin, Y.-H. Chung, J. A. Kim et al. ,"Factors predisposing metastatic tumor antigen 1 overexpression in hepatitis B virus associated hepatocellular carcinoma"Digestive Diseases and Sciences, vol. 57, no. 11, pp. 2917-2923, 2012
9. C.-M. Chu, C.-C. Lin, Y.-C. Chen, W.-J. Jeng, S.-M. Lin, and Y.-F. Liaw,"Basal core promoter mutation is associated with progression to cirrhosis rather than hepatocellular carcinoma in chronic hepatitis B virus infection"British Journal of Cancer, vol. 107, no. 12, pp. 2010-2015, 2012
10. Y.-F. Liaw and C.-M. Chu,"Hepatitis B virus infection"The Lancet, vol. 373, no. 9663, pp. 582-592, 2009
11. S. Murakami,"Hepatitis B virus X protein: a multifunctional viral regulator"Journal of Gastroenterology, vol. 36, no. 10, pp. 651-660, 2001
12. J.-H. Cheong, M.-K. Yi, Y. Lin, and S. Murakami,"Human RPB5, a subunit shared by eukaryotic nuclear RNA polymerases, binds human hepatitis B virus X protein and may play a role in X transactivation"The EMBO Journal, vol. 14, no. 1, pp. 143-150, 1995
13. X. W. Wang, K. Forrester, H. Yeh, M. A. Feitelson, J.-R. Gu, and C. C. Harris,"Hepatitis B virus X protein inhibits p53 sequencespecific DNA binding, transcriptional activity, and association with transcription factor ERCC3"Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 6, pp. 2230-2234, 1994
14. T.-H. Lee, S. J. Elledge, and J. S. Butel,"Hepatitis B virus X protein interacts with a probable cellular DNA repair protein"Journal of Virology, vol. 69, no. 2, pp. 1107-1114, 1995
15. Y.-H. Choi, H.-I. Kim, J. K. Seong et al. ,"Hepatitis B virus X proteinmodulates peroxisome proliferator-Activated receptor through protein-protein interaction"FEBS Letters, vol. 557, no. 1-3, pp. 73-80, 2004
16. Y. Xue, J. Wong, G. T. Moreno, M. K. Young, J. Coté, and W. Wang,"NURD, a novel complex with both ATPdependent chromatin-remodeling and histone deacetylase activities"Molecular Cell, vol. 2, no. 6, pp. 851-861, 1998
17. R. Jiang, L. Deng, L. Zhao et al. ,"miR-22 promotesHBV-related hepatocellular carcinoma development in males"Clinical Cancer Research, vol. 17, no. 17, pp. 5593-5603, 2011
18. N. Hirankarn, I. Kimkong, P. Kummee, P. Tangkijvanich, and Y. Poovorawan,"Interleukin-1beta gene polymorphism associated with hepatocellular carcinoma in hepatitis B virus infection"World Journal of Gastroenterology, vol. 12, no. 5, pp. 776-779, 2006
19. V. W.-S. Wong, J. Yu, A. S.-L. Cheng et al. ,"High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B"International Journal of Cancer, vol. 124, no. 12, pp. 2766-2770, 2009
20. P.-J. Chen, S.-H. Yeh, W.-H. Liu et al. ,"Androgen pathway stimulatesMicroRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis"Hepatology, vol. 56, no. 2, pp. 632-643, 2012
21. Y. Ladeiro, G. Couchy, C. Balabaud et al. ,"MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations"Hepatology, vol. 47, no. 6, pp. 1955-1963, 2008
22. Y. Wang, J. Cheng, C. Xu et al. ,"Quantitative methylation analysis reveals gender and age differences in p16INK4a hypermethylation in hepatitis B virus-related hepatocellular carcinoma"Liver International, vol. 32, no. 3, pp. 420-428, 2012
23. Y. Tian, W. Yang, J. Song, Y. Wu, and B. W. Ni,"Hepatitis B virus X protein-induced aberrant epigenetic modifications contributing to human hepatocellular carcinoma pathogenesis"Molecular and Cellular Biology, vol. 33, no. 15, pp. 2810-2816, 2013
24. S. Baig,"Gender disparity in infections of hepatitis B virus"Journal of theCollege of Physicians and Surgeons-Pakistan, vol. 19, no. 9, pp. 598-600, 2009
25. Z.-Z. Zhu, D. Wang, W.-M. Cong et al. ,"Sex-related differences in DNA copy number alterations in hepatitis B virus-Associated hepatocellular carcinoma"Asian Pacific Journal of Cancer Prevention, vol. 13, no. 1, pp. 225-229, 2012
26. A. Ruggieri, C. Barbati, andW. Malorni,"Cellular and molecular mechanisms involved in hepatocellular carcinoma gender disparity"International Journal of Cancer, vol. 127, no. 3, pp. 499-504, 2010
27. C. Humphries,"Sex differences: luck of the chromosomes"Nature, vol. 516, no. 729, pp. S10-S11, 2014
28. H. B. El-Serag,"Epidemiology of viral hepatitis and hepatocellular carcinoma"Gastroenterology, vol. 142, no. 6, pp. 1264-1273, 2012
29. Y.-T. Huang, C.-L. Jen, H.-I. Yang et al. ,"Lifetime risk and sex difference of hepatocellular carcinoma among patients with chronic hepatitis B and C"Journal of Clinical Oncology, vol. 29, no. 27, pp. 3643-3650, 2011
30. F. Farinati, N. De Maria, C. Marafin, S. Fagiuoli, G. D. Libera, and R. Naccarato,"Hepatocellular carcinoma in alcoholic cirrhosis is sex hormone imbalance a pathogenetic factor"European Journal of Gastroenterology &Hepatology, vol. 7, no. 2, pp. 145-150, 1995
31. M.-W. Yu, H.-C. Chang, S.-C. Chang et al. ,"Role of reproductive factors in hepatocellular carcinoma: impact on hepatitis B-And C-related risk"Hepatology, vol. 38, no. 6, pp. 1393-1400, 2003
32. M.-W. Yu and C.-J. Chen,"Elevated serum testosterone levels and risk of hepatocellular carcinoma"Cancer Research, vol. 53, no. 4, pp. 790-794, 1993
33. F.-H. Su, J.-D. Chen, S.-H. Cheng, C.-H. Lin, Y.-H. Liu, and F.-Y. Chu,"Seroprevalence of Hepatitis-B infection amongst Taiwanese university students 18 years following the commencement of a national Hepatitis-B vaccination program"Journal of Medical Virology, vol. 79, no. 2, pp. 138-143, 2007
34. A. T. Meadows, J. L. Naiman, and M. Valdes-Dapena,"Hepatoma associated with androgen therapy for aplastic anemia"The Journal of Pediatrics, vol. 84, no. 1, pp. 109-110, 1974
35. J. J. Mulvihill, R. L. Ridolfi, F. R. Schultz, M. S. Borzy, and P. B. T. Haughton,"Hepatic adenoma in Fanconi anemia treated with oxymetholone"The Journal of Pediatrics, vol. 87, no. 1, pp. 122-124, 1975
36. H. Farza, A. M. Salmon, M. Hadchouel et al. ,"Hepatitis B surface antigen gene expression is regulated by sex steroids and glucocorticoids in transgenic mice"Proceedings of the National Academy of Sciences of the United States of America, vol. 84, no. 5, pp. 1187-1191, 1987
37. J. A. DeLoia, R. D. Burk, and J. D. Gearhart,"Developmental regulation of hepatitis B surface antigen expression in two lines of hepatitis B virus transgenic mice"Journal of Virology, vol. 63, no. 9, pp. 4069-4073, 1989
38. S. Breidbart, R. D. Burk, and P. Saenger,"Hormonal regulation of hepatitis B virus gene expression: influence of androgen receptor"Pediatric Research, vol. 34, no. 3, pp. 300-302, 1993
39. S.-H. Yeh and P.-J. Chen,"Gender disparity of hepatocellular carcinoma: the roles of sex hormones"Oncology, vol. 78, supplement 1, pp. 172-179, 2010
40. M. Beato and J. Klug,"Steroid hormone receptors: an update"Human Reproduction Update, vol. 6, no. 3, pp. 225-236, 2000
41. S. Yamashita,"Localization and functions of steroid hormone receptors"Histology and Histopathology, vol. 13, no. 1, pp. 255-270, 1998
42. J. Cui, Y. Shen, and R. Li,"Estrogen synthesis and signaling pathways during aging: from periphery to brain"Trends in Molecular Medicine, vol. 19, no. 3, pp. 197-209, 2013
43. C. S. Chang, J. Kokontis, and S. Liao,"Molecular cloning of human and rat complementary DNA encoding androgen receptors"Science, vol. 240, no. 4850, pp. 324-326, 1988
44. F. Claessens, G. Verrijdt, E. Schoenmakers et al. ,"SelectiveDNA binding by the androgen receptor as a mechanism for hormonespecific gene regulation"Journal of Steroid Biochemistry and Molecular Biology, vol. 76, no. 1-5, pp. 23-30, 2001
45. S. Yeh, H.-C. Chang, H. Miyamoto et al. ,"Differential induction of the androgen receptor transcriptional activity by selective androgen receptor coactivators"The Keio Journal of Medicine, vol. 48, no. 2, pp. 87-92, 1999
46. E. G. Bluemn and P. S. Nelson,"The androgen/androgen receptor axis in prostate cancer"Current Opinion in Oncology, vol. 24, no. 3, pp. 251-257, 2012
47. T. Nakatani, G. Roy, N. Fujimoto, T. Asahara, and A. Ito,"Sex hormone dependency of diethylnitrosamine-induced liver tumors in mice and chemoprevention by leuprorelin"Japanese Journal of Cancer Research, vol. 92, no. 3, pp. 249-256, 2001
48. W.-L. Ma, C.-L. Hsu, M.-H. Wu et al. ,"Androgen receptor is a new potential therapeutic target for the treatment of hepatocellular carcinoma"Gastroenterology, vol. 135, no. 3, pp. 947. e5-955. e5, 2008
49. C. Rinaldi, A. Lesmana, and L. A. Lesmana,"The role of liver biopsy in the non-invasive methods era and liver stiffness measurement using transient elastography"in Liver Biopsy, H. Takahashi, Ed. , chapter 1, InTech, Rijeka, Croatia, 2011
50. D. L. Ahlbory-Dieker, B. D. Stride, G. Leder et al. ,"DNA binding by estrogen receptor-is essential for the transcriptional response to estrogen in the liver and the uterus"Molecular Endocrinology, vol. 23, no. 10, pp. 1544-1555, 2009
51. D. J. Waxman and M. G. Holloway,"Sex differences in the expression of hepatic drug metabolizing enzymes"Molecular Pharmacology, vol. 76, no. 2, pp. 215-228, 2009
52. M. Kalra, J. Mayes, S. Assefa, A. K. Kaul, and R. Kaul,"Role of sex steroid receptors in pathobiology of hepatocellular carcinoma"World Journal of Gastroenterology, vol. 14, no. 39, pp. 5945-5961, 2008
53. M.-H. Wu, W.-L. Ma, C.-L. Hsu et al. ,"Androgen receptor promotes hepatitis B virus-induced hepatocarcinogenesis through modulation of hepatitis B virus RNA transcription"Science Translational Medicine, vol. 2, no. 32, pp. 32-35, 2010
54. S.-H. Wang, S.-H. Yeh, W.-H. Lin, H.-Y. Wang, D.-S. Chen, and P.-J. Chen,"Identification of androgen response elements in the enhancer I of hepatitis B virus: a mechanism for sex disparity in chronic hepatitis B"Hepatology, vol. 50, no. 5, pp. 1392-1402, 2009
55. W.-J. Yang, C.-J. Chang, S.-H. Yeh et al. ,"Hepatitis B virus X protein enhances the transcriptional activity of the androgen receptor through c-Src and glycogen synthase kinase-3 kinase pathways"Hepatology, vol. 49, no. 5, pp. 1515-1524, 2009
56. M. J. Bouchard, L. Wang, and R. J. Schneider,"Activation of focal adhesion kinase by hepatitis B virus HBx protein:multiple functions in viral replication"Journal of Virology, vol. 80, no. 9, pp. 4406-4414, 2006
57. Q. Ding, W. Xia, J.-C. Liu et al. ,"Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of betacatenin"Molecular Cell, vol. 19, no. 2, pp. 159-170, 2005
58. H. Feng, A. S. L. Cheng, D. P. Tsang et al. ,"Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives-catenin/T cell factor-dependent hepatocarcinogenesis"The Journal of Clinical Investigation, vol. 121, no. 8, pp. 3159-3175, 2011
59. X. Tan, U. Apte, A. Micsenyi et al. ,"Epidermal growth factor receptor: a novel target of the Wnt/beta-catenin pathway in liver"Gastroenterology, vol. 129, no. 1, pp. 285-302, 2005
60. W. S. Moon, H. S. Park, K. H. Yu et al. ,"Expression of betacellulin and epidermal growth factor receptor in hepatocellular carcinoma: implications for angiogenesis"Human Pathology, vol. 37, no. 10, pp. 1324-1332, 2006
61. S.-I. Ueda, Y. Basaki, M. Yoshie et al. ,"PTEN/Akt signaling through epidermal growth factor receptor is prerequisite for angiogenesis by hepatocellular carcinoma cells that is susceptible to inhibition by gefitinib"Cancer Research, vol. 66, no. 10, pp. 5346-5353, 2006
62. Y. Almog, A. Klein, R. Adler, O. Laub, and R. Tur-Kaspa,"Estrogen suppresses hepatitis B virus expression in male athymic mice transplanted with HBV transfected Hep G-2 cells"Antiviral Research, vol. 19, no. 4, pp. 285-293, 1992
63. N. D. Maria, M. Manno, and E. Villa,"Sex hormones and liver cancer"Molecular and Cellular Endocrinology, vol. 193, no. 1-2, pp. 59-63, 2002
64. S.-H. Wang, S.-H. Yeh, W.-H. Lin et al. ,"Estrogen receptor represses transcription of HBV genes via interaction with hepatocyte nuclear factor 4"Gastroenterology, vol. 142, no. 4, pp. 989. e4-998. e4, 2012
65. B. S. Katzenellenbogen and J. A. Katzenellenbogen,"Estrogen receptor transcription and transactivation: estrogen receptor alpha and estrogen receptor beta: regulation by selective estrogen receptor modulators and importance in breast cancer"Breast Cancer Research, vol. 2, no. 5, pp. 335-344, 2000
66. S. Tong,"Hepatitis B virus, a sex hormone-responsive virus"Gastroenterology, vol. 142, no. 4, pp. 696-699, 2012
67. J. Han, L. Ding, B. Yuan et al. ,"Hepatitis B virus X protein and the estrogen receptor variant lacking exon 5 inhibit estrogen receptor signaling in hepatoma cells"Nucleic Acids Research, vol. 34, no. 10, pp. 3095-3106, 2006
68. G. A. Calin and C. M. Croce,"MicroRNA signatures in human cancers"Nature Reviews Cancer, vol. 6, no. 11, pp. 857-866, 2006
69. A. Petri, M. Lindow, and S. Kauppinen,"MicroRNA silencing in primates: towards development of novel therapeutics"Cancer Research, vol. 69, no. 2, pp. 393-395, 2009
70. Y. Murakami, T. Yasuda, K. Saigo et al. ,"Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues"Oncogene, vol. 25, no. 17, pp. 2537-2545, 2006
71. J. L. Mott,"MicroRNAs involved in tumor suppressor and oncogene pathways: implications for hepatobiliary neoplasia"Hepatology, vol. 50, no. 2, pp. 630-637, 2009
72. R. Visone, F. Petrocca, and C. M. Croce,"Micro-RNAs in gastrointestinal and liver disease"Gastroenterology, vol. 135, no. 6, pp. 1866-1869, 2008
73. P. Gao, C. C.-L. Wong, E. K.-K. Tung, J. M.-F. Lee, C.-M. Wong, and I. O.-L. Ng,"Deregulation of microRNA expression occurs early and accumulates in early stages of HBV-Associated multistep hepatocarcinogenesis"Journal of Hepatology, vol. 54, no. 6, pp. 1177-1184, 2011
74. C.-P. Lin, Y. J. Choi, G. G. Hicks, and L. He,"The emerging functions of the p53-miRNA network in stem cell biology"Cell Cycle, vol. 11, no. 11, pp. 2063-2072, 2012
75. N. Xu, T. Papagiannakopoulos, G. Pan, J. A. Thomson, andK. S. Kosik,"MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells"Cell, vol. 137, no. 4, pp. 647-658, 2009
76. P. Xuan, K. Han, M. Guo et al. ,"Prediction of microRNAs associated with human diseases based on weighted k most similar neighbors"PLoS ONE, vol. 8, no. 8, Article ID e70204, 2013
77. Y. Ma, W. Bao-Han, X. Lv et al. ,"MicroRNA-34amediates the autocrine signaling of PAR2-Activating proteinase and its role in colonic cancer cell proliferation"PLoSONE, vol. 8, no. 8, Article ID e72383, 2013
78. C.-M. Chiu, S.-H. Yeh, P.-J. Chen et al. ,"Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level"Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 8, pp. 2571-2578, 2007
79. W. E. Naugler, T. Sakurai, S. Kim et al. ,"Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production"Science, vol. 317, no. 5834, pp. 121-124, 2007
80. H. Nakagawa and S. Maeda,"Inflammation-And stress-related signaling pathways in hepatocarcinogenesis"World Journal of Gastroenterology, vol. 18, no. 31, pp. 4071-4081, 2012
81. D. P. Pandey and D. Picard,"miR-22 inhibits estrogen signaling by directly targeting the estrogen receptor alpha mRNA"Molecular and Cellular Biology, vol. 29, no. 13, pp. 3783-3790, 2009
82. W.-H. Liu, S.-H. Yeh, C.-C. Lu et al. ,"MicroRNA-18a prevents estrogen receptor-Alpha expression, promoting proliferation of hepatocellular carcinoma cells"Gastroenterology, vol. 136, no. 2, pp. 683-693, 2009
83. C.-L. Li, K.-H. Yeh, W.-H. Liu et al. ,"Elevated p53 promotes the processing of miR-18a to decrease estrogen receptor-in female hepatocellular carcinoma"International Journal of Cancer, vol. 136, no. 4, pp. 761-770, 2015
84. C.-S. Wu, C.-J. Yen, R.-H. Chou et al. ,"Downregulation of microRNA-15b by hepatitis B virus X enhances hepatocellular carcinoma proliferation via fucosyltransferase 2-induced Globo Hexpression"International Journal of Cancer, vol. 134, no. 7, pp. 1638-1647, 2014
85. H. B. El-Serag,"Epidemiology of hepatocellular carcinoma"Clinics in Liver Disease, vol. 5, no. 1, pp. 87-107, 2001
86. S. Schaedler, J. Krause, K. Himmelsbach et al. ,"Hepatitis B virus induces expression of antioxidant response element-regulated genes by activation ofNrf2, "The Journal of Biological Chemistry, vol. 285, no. 52, pp. 41074-41086, 2010
87. R. Dayoub, A. Vogel, J. Schuett et al. ,"Nrf2 activates augmenter of liver regeneration (ALR) via antioxidant response element and links oxidative stress to liver regeneration"Molecular Medicine, vol. 19, no. 28, pp. 237-244, 2013
88. S.-L. Yang, C. Yu, J.-X. Jiang, L.-P. Liu, X. Fang, and C. Wu,"Hepatitis B virus X protein disrupts the balance of the expression of circadian rhythm genes in hepatocellular carcinoma"Oncology Letters, vol. 8, no. 6, pp. 2715-2720, 2014
89. L. Fu and C. C. Lee,"The circadian clock: pacemaker and tumour suppressor"Nature Reviews Cancer, vol. 3, no. 5, pp. 350-361, 2003
90. J. M. Llovet,"Updated treatment approach to hepatocellular carcinoma"Journal of Gastroenterology, vol. 40, no. 3, pp. 225-235, 2005
91. S. Mandlekar and A.-N. T. Kong,"Mechanisms of tamoxifeninduced apoptosis"Apoptosis, vol. 6, no. 6, pp. 469-477, 2001
92. R. Guo, T. Wang, H. Shen et al. ,"Involvement of mTOR and survivin inhibition in tamoxifen-induced apoptosis in human hepatoblastoma cell line HepG2"Biomedicine and Pharmacotherapy, vol. 64, no. 4, pp. 249-253, 2010
93. P. K. H. Chow, B.-C. Tai, C.-K. Tan et al. ,"High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: a multicenter randomized controlled trial"Hepatology, vol. 36, no. 5, pp. 1221-1226, 2002
94. E. Villa, A. Colantoni, A. Grottola et al. ,"Variant estrogen receptors and their role in liver disease, "Molecular and Cellular Endocrinology, vol. 193, no. 1-2, pp. 65-69, 2002
95. Y. Chao, W.-K. Chan, Y.-S. Huang et al. ,"Phase II study of flutamide in the treatment of hepatocellular carcinoma"Cancer, vol. 77, no. 4, pp. 635-639, 1996.