Epithelial-mesenchymal transition: molecular pathways of hepatitis viruses-induced hepatocellular carcinoma progression

Tumor Biology

Volumn 35, Issue 8, 2014, Pages 7307-7315

  Panebianco, Concetta ^a   Saracino, Chiara ^a   Pazienza, Valerio ^a  

^a CASA SOLLIEVO DELLA SOFFERENZA HOSPITAL   (Italy)

Author keywords

EMT; HBV; HCV; HDV

Indexed keywords

CARCINOMA, HEPATOCELLULAR; COMPLICATION; DELTA AGENT HEPATITIS; DISEASE COURSE; EPITHELIAL MESENCHYMAL TRANSITION; HEPATITIS B; HEPATITIS C; HUMAN; LIVER NEOPLASMS; PATHOLOGY; VIRUS HEPATITIS;

CARCINOMA, HEPATOCELLULAR; DISEASE PROGRESSION; EPITHELIAL-MESENCHYMAL TRANSITION; HEPATITIS B; HEPATITIS C; HEPATITIS D; HEPATITIS, VIRAL, HUMAN; HUMANS; LIVER NEOPLASMS;

EID: 84922393801     PISSN: 10104283     EISSN: None     Source Type: Journal    
DOI: 10.1007/s13277-014-2075-x     Document Type: Review

References (117)

1. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365:1118–27.
2. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379:1245–55.
3. Gomaa AI, Khan SA, Toledano MB, Waked I, Taylor-Robinson SD. Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J Gastroenterol. 2008;14:4300–8.
4. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.
5. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6:674–87.
6. Bartosch B. Hepatitis B and C viruses and hepatocellular carcinoma. Viruses. 2010;2:1504–9.
7. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264–73. e1261.
8. Abbas Z, Qureshi M, Hamid S, Jafri W. Hepatocellular carcinoma in hepatitis D: does it differ from hepatitis B monoinfection? Saudi J Gastroenterol. 2012;18:18–22.
9. Ji J, Sundquist K, Sundquist J. A population-based study of hepatitis D virus as potential risk factor for hepatocellular carcinoma. J Natl Cancer Inst. 2012;104:790–2.
10. Romeo R, Del Ninno E, Rumi M, Russo A, Sangiovanni A, de Franchis R, et al. A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology. 2009;136:1629–38.
11. Verme G, Brunetto MR, Oliveri F, Baldi M, Forzani B, Piantino P, et al. Role of hepatitis delta virus infection in hepatocellular carcinoma. Dig Dis Sci. 1991;36:1134–6.
12. Bouchard MJ, Navas-Martin S. Hepatitis B and C virus hepatocarcinogenesis: lessons learned and future challenges. Cancer Lett. 2011;305:123–43.
13. Levrero M. Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene. 2006;25:3834–47.
14. Ripoli M, Barbano R, Balsamo T, Piccoli C, Brunetti V, Coco M, et al. Hypermethylated levels of E-cadherin promoter in Huh-7 cells expressing the HCV core protein. Virus Res. 2011;160:74–81.
15. Rongrui L, Na H, Zongfang L, Fanpu J, Shiwen J: Epigenetic mechanism involved in the HBV/HCV-related hepatocellular carcinoma tumorigenesis. Curr Pharm Des 2013.
16. Block TM, Mehta AS, Fimmel CJ, Jordan R. Molecular viral oncology of hepatocellular carcinoma. Oncogene. 2003;22:5093–107.
17. Shimoda R, Nagashima M, Sakamoto M, Yamaguchi N, Hirohashi S, Yokota J, et al. Increased formation of oxidative DNA damage, 8-hydroxydeoxyguanosine, in human livers with chronic hepatitis. Cancer Res. 1994;54:3171–2.
18. Hagen TM, Huang S, Curnutte J, Fowler P, Martinez V, Wehr CM, et al. Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma. Proc Natl Acad Sci U S A. 1994;91:12808–12.
19. Moriya K, Fujie H, Shintani Y, Yotsuyanagi H, Tsutsumi T, Ishibashi K, et al. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med. 1998;4:1065–7.
20. Moriya K, Nakagawa K, Santa T, Shintani Y, Fujie H, Miyoshi H, et al. Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res. 2001;61:4365–70.
21. Lin S, Hoffmann K, Schemmer P. Treatment of Hepatocellular Carcinoma: A Systematic Review. Liver Cancer. 2012;1:144–58.
22. Vivarelli M, Montalti R, Risaliti A. Multimodal treatment of hepatocellular carcinoma on cirrhosis: an update. World J Gastroenterol. 2013;19:7316–26.
23. Xie B, Wang DH, Spechler SJ. Sorafenib for treatment of hepatocellular carcinoma: a systematic review. Dig Dis Sci. 2012;57:1122–9.
24. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.
25. Gauthier A, Ho M. Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update. Hepatol Res. 2013;43:147–54.
26. Lee HS. Management of patients with hepatocellular carcinoma and extrahepatic metastasis. Dig Dis. 2011;29:333–8.
27. Wang C, Jiang K, Kang X, Gao D, Sun C, Li Y, et al. Tumor-derived secretory clusterin induces epithelial-mesenchymal transition and facilitates hepatocellular carcinoma metastasis. Int J Biochem Cell Biol. 2012;44:2308–20.
28. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.
29. Firrincieli D, Boissan M, Chignard N. Epithelial-mesenchymal transition in the liver. Gastroenterol Clin Biol. 2010;34:523–8.
30. Lamouille S, Derynck R. Emergence of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin axis in transforming growth factor-beta-induced epithelial-mesenchymal transition. Cells Tissues Organs. 2010;193:8–22.
31. van Zijl F, Zulehner G, Petz M, Schneller D, Kornauth C, Hau M, et al. Epithelial-mesenchymal transition in hepatocellular carcinoma. Futur Oncol. 2009;5:1169–79.
32. Yang G, Yuan J, Li K. EMT transcription factors: implication in osteosarcoma. Med Oncol. 2013;30:697.
33. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009;119:1429–37.
34. Arora P, Kim EO, Jung JK, Jang KL. Hepatitis C virus core protein downregulates E-cadherin expression via activation of DNA methyltransferase 1 and 3b. Cancer Lett. 2008;261:244–52.
35. Orlichenko LS, Radisky DC. Matrix metalloproteinases stimulate epithelial-mesenchymal transition during tumor development. Clin Exp Metastasis. 2008;25:593–600.
36. Buendia MA. Genetics of hepatocellular carcinoma. Semin Cancer Biol. 2000;10:185–200.
37. Schmalhofer O, Brabletz S, Brabletz T. E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev. 2009;28:151–66.
38. Wu WS. The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev. 2006;25:695–705.
39. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119:1420–8.
40. Yao D, Dai C, Peng S. Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res. 2011;9:1608–20.
41. Mima K, Hayashi H, Kuroki H, Nakagawa S, Okabe H, Chikamoto A, et al. Epithelial-mesenchymal transition expression profiles as a prognostic factor for disease-free survival in hepatocellular carcinoma: clinical significance of transforming growth factor-beta signaling. Oncol Lett. 2013;5:149–54.
42. Miyoshi A, Kitajima Y, Kido S, Shimonishi T, Matsuyama S, Kitahara K, et al. Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma. Br J Cancer. 2005;92:252–8.
43. Sugimachi K, Tanaka S, Kameyama T, Taguchi K, Aishima S, Shimada M, et al. Transcriptional repressor snail and progression of human hepatocellular carcinoma. Clin Cancer Res. 2003;9:2657–64.
44. Yang MH, Chen CL, Chau GY, Chiou SH, Su CW, Chou TY, et al. Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma. Hepatology. 2009;50:1464–74.
45. Cao GW. Clinical relevance and public health significance of hepatitis B virus genomic variations. World J Gastroenterol. 2009;15:5761–9.
46. Shi YH. Correlation between hepatitis B virus genotypes and clinical outcomes. Jpn J Infect Dis. 2012;65:476–82.
47. Ayub A, Ashfaq UA, Haque A. HBV induced HCC: major risk factors from genetic to molecular level. Biomed Res Int. 2013;2013:810461.
48. Wei Y, Neuveut C, Tiollais P, Buendia MA. Molecular biology of the hepatitis B virus and role of the X gene. Pathol Biol (Paris). 2010;58:267–72.
49. Ng SA, Lee C. Hepatitis B virus X gene and hepatocarcinogenesis. J Gastroenterol. 2011;46:974–90.
50. Brechot C. Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: old and new paradigms. Gastroenterology. 2004;127:S56–61.
51. Lara-Pezzi E, Majano PL, Yanez-Mo M, Gomez-Gonzalo M, Carretero M, Moreno-Otero R, et al. Effect of the hepatitis B virus HBx protein on integrin-mediated adhesion to and migration on extracellular matrix. J Hepatol. 2001;34:409–15.
52. Lara-Pezzi E, Roche S, Andrisani OM, Sanchez-Madrid F, Lopez-Cabrera M. The hepatitis B virus HBx protein induces adherens junction disruption in a src-dependent manner. Oncogene. 2001;20:3323–31.
53. Lee TK, Man K, Poon RT, Lo CM, Yuen AP, Ng IO, et al. Signal transducers and activators of transcription 5b activation enhances hepatocellular carcinoma aggressiveness through induction of epithelial-mesenchymal transition. Cancer Res. 2006;66:9948–56.
54. Teng J, Wang X, Xu Z, Tang N. HBx-dependent activation of Twist mediates STAT3 control of epithelium-mesenchymal transition of liver cells. J Cell Biochem. 2013;114:1097–104.
55. Gao B, Wang H, Lafdil F, Feng D. STAT proteins—key regulators of anti-viral responses, inflammation, and tumorigenesis in the liver. J Hepatol. 2012;57:430–41.
56. Yu H, Jove R. The STATs of cancer—new molecular targets come of age. Nat Rev Cancer. 2004;4:97–105.
57. Haura EB, Turkson J, Jove R. Mechanisms of disease: insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol. 2005;2:315–24.
58. Liu H, Xu L, He H, Zhu Y, Liu J, Wang S, et al. Hepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing Snail protein. Cancer Sci. 2012;103:2072–81.
59. Yang SZ, Zhang LD, Zhang Y, Xiong Y, Zhang YJ, Li HL, et al. HBx protein induces EMT through c-Src activation in SMMC-7721 hepatoma cell line. Biochem Biophys Res Commun. 2009;382:555–60.
60. Liang J, Slingerland JM. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle. 2003;2:339–45.
61. Lee CG, Ren J, Cheong IS, Ban KH, Ooi LL. Yong Tan S, Kan A, Nuchprayoon I, Jin R, Lee KH, Choti M, Lee LA: Expression of the FAT10 gene is highly upregulated in hepatocellular carcinoma and other gastrointestinal and gynecological cancers. Oncogene. 2003;22:2592–603.
62. Lukasiak S, Schiller C, Oehlschlaeger P, Schmidtke G, Krause P, Legler DF, et al. Proinflammatory cytokines cause FAT10 upregulation in cancers of liver and colon. Oncogene. 2008;27:6068–74.
63. Qing X, French BA, Oliva J, French SW. Increased expression of FAT10 in colon benign, premalignant and malignant epithelial neoplasms. Exp Mol Pathol. 2011;90:51–4.
64. Liu L, Dong Z, Liang J, Cao C, Sun J, Ding Y, Wu D: As an independent prognostic factor, FAT10 promotes hepatitis B virus-related hepatocellular carcinoma progression via Akt/GSK3beta pathway. Oncogene 2013
65. Liu J, Lian Z, Han S, Waye MM, Wang H, Wu MC, et al. Downregulation of E-cadherin by hepatitis B virus X antigen in hepatocellular carcinoma. Oncogene. 2006;25:1008–17.
66. Arzumanyan A, Friedman T, Kotei E, Ng IO, Lian Z, Feitelson MA. Epigenetic repression of E-cadherin expression by hepatitis B virus x antigen in liver cancer. Oncogene. 2012;31:563–72.
67. Xu X, Fan Z, Kang L, Han J, Jiang C, Zheng X, et al. Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis. J Clin Invest. 2013;123:630–45.
68. Na DC, Lee JE, Yoo JE, Oh BK, Choi GH, Park YN. Invasion and EMT-associated genes are up-regulated in B viral hepatocellular carcinoma with high expression of CD133-human and cell culture study. Exp Mol Pathol. 2011;90:66–73.
69. Ai J, Tang Q, Wu Y, Xu Y, Feng T, Zhou R, et al. The role of polymeric immunoglobulin receptor in inflammation-induced tumor metastasis of human hepatocellular carcinoma. J Natl Cancer Inst. 2011;103:1696–712.
70. Chen JS, Su IJ, Leu YW, Young KC, Sun HS. Expression of T-cell lymphoma invasion and metastasis 2 (TIAM2) promotes proliferation and invasion of liver cancer. Int J Cancer. 2012;130:1302–13.
71. Ripoli M, Pazienza V. Impact of HCV genetic differences on pathobiology of disease. Expert Rev Anti Infect Ther. 2011;9:747–59.
72. Abid K, Pazienza V, de Gottardi A, Rubbia-Brandt L, Conne B, Pugnale P, et al. An in vitro model of hepatitis C virus genotype 3a-associated triglycerides accumulation. J Hepatol. 2005;42:744–51.
73. Pazienza V, Clement S, Pugnale P, Conzelman S, Foti M, Mangia A, et al. The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms. Hepatology. 2007;45:1164–71.
74. Pazienza V, Clement S, Pugnale P, Conzelman S, Pascarella S, Mangia A, et al. Gene expression profile of Huh-7 cells expressing hepatitis C virus genotype 1b or 3a core proteins. Liver Int. 2009;29:661–9.
75. Bartenschlager R, Lohmann V. Replication of the hepatitis C virus. Baillieres Best Pract Res Clin Gastroenterol. 2000;14:241–54.
76. Shrivastava S, Mukherjee A, Ray RB. Hepatitis C virus infection, microRNA and liver disease progression. World J Hepatol. 2013;5:479–86.
77. Fraser J, Boo I, Poumbourios P, Drummer HE. Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 contain reduced cysteine residues essential for virus entry. J Biol Chem. 2011;286:31984–92.
78. Lavie M, Goffard A, Dubuisson J: HCV Glycoproteins: assembly of a functional E1-E2 heterodimer. 2006
79. Polyak SJ, Klein KC, Shoji I, Miyamura T, Lingappa JR: Assemble and interact: pleiotropic functions of the HCV core protein. 2006
80. Gentzsch J, Brohm C, Steinmann E, Friesland M, Menzel N, Vieyres G, et al. Hepatitis c Virus p7 is critical for capsid assembly and envelopment. PLoS Pathog. 2013;9:e1003355.
81. Welbourn S, Pause A: HCV NS2/3 protease. 2006
82. Lin C: HCV NS3-4A Serine protease. 2006
83. Sklan EH, Glenn JS: HCV NS4B: from obscurity to central stage. 2006
84. Schmitz U, Tan SL. NS5A—from obscurity to new target for HCV therapy. Recent Pat Antiinfect Drug Discov. 2008;3:77–92.
85. Ranjith-Kumar CT, Kao CC: Biochemical activities of the HCV NS5B RNA-dependent RNA polymerase. 2006
86. Jeong SW, Jang JY, Chung RT. Hepatitis C virus and hepatocarcinogenesis. Clin Mol Hepatol. 2012;18:347–56.
87. McGivern DR, Lemon SM. Virus-specific mechanisms of carcinogenesis in hepatitis C virus associated liver cancer. Oncogene. 2011;30:1969–83.
88. Bose SK, Meyer K, Di Bisceglie AM, Ray RB, Ray R. Hepatitis C virus induces epithelial-mesenchymal transition in primary human hepatocytes. J Virol. 2012;86:13621–8.
89. Iqbal J, McRae S, Mai T, Banaudha K, Sarkar-Dutta M, Waris G. Role of hepatitis C virus induced osteopontin in epithelial to mesenchymal transition, migration and invasion of hepatocytes. PLoS One. 2014;9:e87464.
90. Iqbal J, McRae S, Banaudha K, Mai T, Waris G. Mechanism of hepatitis C virus (HCV)-induced osteopontin and its role in epithelial to mesenchymal transition of hepatocytes. J Biol Chem. 2013;288:36994–7009.
91. Anborgh PH, Mutrie JC, Tuck AB, Chambers AF. Role of the metastasis-promoting protein osteopontin in the tumour microenvironment. J Cell Mol Med. 2010;14:2037–44.
92. Rangaswami H, Bulbule A, Kundu GC. Osteopontin: role in cell signaling and cancer progression. Trends Cell Biol. 2006;16:79–87.
93. Dooley S, ten Dijke P. TGF-beta in progression of liver disease. Cell Tissue Res. 2012;347:245–56.
94. Kubiczkova L, Sedlarikova L, Hajek R, Sevcikova S. TGF-beta—an excellent servant but a bad master. J Transl Med. 2012;10:183.
95. Akhurst RJ, Derynck R. TGF-beta signaling in cancer—a double-edged sword. Trends Cell Biol. 2001;11:S44–51.
96. Heldin CH, Vanlandewijck M, Moustakas A. Regulation of EMT by TGFbeta in cancer. FEBS Lett. 2012;586:1959–70.
97. Battaglia S, Benzoubir N, Nobilet S, Charneau P, Samuel D, Zignego AL, et al. Liver cancer-derived hepatitis C virus core proteins shift TGF-beta responses from tumor suppression to epithelial-mesenchymal transition. PLoS One. 2009;4:e4355.
98. Pavio N, Battaglia S, Boucreux D, Arnulf B, Sobesky R, Hermine O, et al. Hepatitis C virus core variants isolated from liver tumor but not from adjacent non-tumor tissue interact with Smad3 and inhibit the TGF-beta pathway. Oncogene. 2005;24:6119–32.
99. Quan H, Zhou F, Nie D, Chen Q, Cai X, Shan X, Zhou Z, Chen K, Huang A, Li S, Tang N: Hepatitis C virus core protein epigenetically silences SFRP1 and enhances HCC aggressiveness by inducing epithelial-mesenchymal transition. Oncogene 2013
100. Benegiamo G, Vinciguerra M, Mazzoccoli G, Piepoli A, Andriulli A, Pazienza V. DNA methyltransferases 1 and 3b expression in Huh-7 cells expressing HCV core protein of different genotypes. Dig Dis Sci. 2012;57:1598–603.
101. Li T, Li D, Cheng L, Wu H, Gao Z, Liu Z, et al. Epithelial-mesenchymal transition induced by hepatitis C virus core protein in cholangiocarcinoma. Ann Surg Oncol. 2010;17:1937–44.
102. Moon HJ, Finney J, Xu L, Moore D, Welch DR, Mure M. MCF-7 cells expressing nuclear associated lysyl oxidase-like 2 (LOXL2) exhibit an epithelial-to-mesenchymal transition (EMT) phenotype and are highly invasive in vitro. J Biol Chem. 2013;288:30000–8.
103. Peinado H, Del Carmen Iglesias-de la Cruz M, Olmeda D, Csiszar K, Fong KS, Vega S, et al. A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. Embo J. 2005;24:3446–58.
104. Verga-Gerard A, Porcherot M, Meyniel-Schicklin L, Andre P, Lotteau V, Perrin-Cocon L. Hepatitis C virus/human interactome identifies SMURF2 and the viral protease as critical elements for the control of TGF-beta signaling. Faseb J. 2013;27:4027–40.
105. Akkari L, Gregoire D, Floc'h N, Moreau M, Hernandez C, Simonin Y, et al. Hepatitis C viral protein NS5A induces EMT and participates in oncogenic transformation of primary hepatocyte precursors. J Hepatol. 2012;57:1021–8.
106. Alves C, Branco C, Cunha C. Hepatitis delta virus: a peculiar virus. Adv Virol. 2013;2013:560105.
107. Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. Lancet. 2011;378:73–85.
108. Rizzetto M, Canese MG, Arico S, Crivelli O, Trepo C, Bonino F, et al. Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut. 1977;18:997–1003.
109. Tseng CH, Lai MM. Hepatitis delta virus RNA replication. Viruses. 2009;1:818–31.
110. Le Gal F, Gault E, Ripault MP, Serpaggi J, Trinchet JC, Gordien E, et al. Eighth major clade for hepatitis delta virus. Emerg Infect Dis. 2006;12:1447–50.
111. Shih HH, Sheen IJ, Su CW, Peng WL, Lin LH, Wu JC. Hepatitis D virus isolates with low replication and epithelial-mesenchymal transition-inducing activity are associated with disease remission. J Virol. 2011;86:9044–54.
112. Choi SH, Jeong SH, Hwang SB. Large hepatitis delta antigen modulates transforming growth factor-beta signaling cascades: implication of hepatitis delta virus-induced liver fibrosis. Gastroenterology. 2007;132:343–57.
113. Benegiamo G, Vinciguerra M, Guarnieri V, Niro GA, Andriulli A, Pazienza V. Hepatitis delta virus induces specific DNA methylation processes in Huh-7 liver cancer cells. FEBS Lett. 2013;587:1424–8.
114. Chen YL, Lv J, Ye XL, Sun MY, Xu Q, Liu CH, et al. Sorafenib inhibits transforming growth factor beta1-mediated epithelial-mesenchymal transition and apoptosis in mouse hepatocytes. Hepatology. 2011;53:1708–18.
115. Nagai T, Arao T, Furuta K, Sakai K, Kudo K, Kaneda H, et al. Sorafenib inhibits the hepatocyte growth factor-mediated epithelial mesenchymal transition in hepatocellular carcinoma. Mol Cancer Ther. 2011;10:169–77.
116. Smolle E, Taucher V, Petru E, Haybaeck J. Targeted treatment of ovarian cancer—the multiple-kinase-inhibitor sorafenib as a potential option. Anticancer Res. 2014;34:1519–30.
117. Zhang J, Chen YL, Ji G, Fang W, Gao Z, Liu Y, et al. Sorafenib inhibits epithelial-mesenchymal transition through an epigenetic-based mechanism in human lung epithelial cells. PLoS One. 2013;8:e64954.