miRNA in hepatocellular carcinoma

Hepatology Research

Volumn 45, Issue 2, 2015, Pages 128-141

  Morishita, Asahiro ^a   Masaki, Tsutomu ^a  

^a KAGAWA UNIVERSITY   (Japan)

Author keywords

Diagnostic and prognostic markers; Hepatocellular carcinoma; MiRNA; Therapeutic target

Indexed keywords

ANTINEOPLASTIC AGENT; ARGONAUTE 2 PROTEIN; CASPASE 3; CYCLIN D2; CYCLIN E; DOXORUBICIN; EPHRIN RECEPTOR A4; EXPORTIN 5; FLUOROURACIL; GELATINASE A; HIGH MOBILITY GROUP A2 PROTEIN; INTERFERON; INTERLEUKIN 6; MESSENGER RNA; METFORMIN; MICRORNA; MICRORNA 124; MICRORNA 221; MICRORNA 26A; OSTEONECTIN; POLO LIKE KINASE 1; PROTEIN BCL W; PROTEIN BCL XL; RNA INDUCED SILENCING COMPLEX; RNA POLYMERASE II; SIRTUIN 1; STAT3 PROTEIN; STROMELYSIN 3; TRANSCRIPTION FACTOR EZH2; VASCULOTROPIN A;

ANGIOGENESIS; APOPTOSIS; AUTOPHAGY; BIOGENESIS; CANCER CHEMOTHERAPY; CANCER INCIDENCE; CANCER PROGNOSIS; CANCER RECURRENCE; CANCER RESISTANCE; CANCER RISK; CELL CYCLE REGULATION; CELL GROWTH; CELL INVASION; CELL PROLIFERATION; DNA METHYLATION; DRUG SENSITIVITY; GENETIC RISK; GENOME ANALYSIS; GLUCONEOGENESIS; HUMAN; LIVER CARCINOGENESIS; LIVER CELL CARCINOMA; METASTASIS; MULTIDRUG RESISTANCE; NONHUMAN; PRIORITY JOURNAL; REVIEW; RNA DEGRADATION; RNA PROCESSING; SINGLE NUCLEOTIDE POLYMORPHISM; TRANSLATION REGULATION;

EID: 84921614011     PISSN: 13866346     EISSN: 1872034X     Source Type: Journal    
DOI: 10.1111/hepr.12386     Document Type: Review

References (203)

1. Zamore PD, Haley B. Ribo-gnome: the big world of small RNAs. Science 2005; 309: 1519-1524.
2. Suzuki H, Maruyama R, Yamamoto E, Kai M. Epigenetic alteration and microRNA dysregulation in cancer. Front Genet 2013; 4: 258.
3. Masaki T. MicroRNA and hepatocellular carcinoma. Hepatol Res 2009; 39: 751-752.
4. Davis-Dusenbery BN, Hata A. MicroRNA in cancer: the involvement of aberrant MicroRNA biogenesis regulatory pathways. Genes Cancer 2010; 1: 1100-1114.
5. Farazi TA, Hoell JI, Morozov P, Tuschl T. MicroRNAs in human cancer. Adv Exp Med Biol 2013; 774: 1-20.
6. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281-297.
7. Krek A, Grun D, Poy MN etal. Combinatorial microRNA target predictions. Nat Genet 2005; 37: 495-500.
8. Griffiths-Jones S. miRBase: microRNA sequences and annotation. Curr Protoc Bioinformatics 2010; Chapter 12: Unit 12 9: 1-0.
9. Michael MZ, SM OC, van Holst Pellekaan NG, Young GP, James RJ. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res 2003; 1: 882-891.
10. Lee EJ, Gusev Y, Jiang J etal. Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer 2007; 120: 1046-1054.
11. Takamizawa J, Konishi H, Yanagisawa K etal. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 2004; 64: 3753-3756.
12. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 2007; 133: 647-658.
13. Calin GA, Sevignani C, Dumitru CD etal. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A 2004; 101: 2999-3004.
14. Calin GA, Dumitru CD, Shimizu M etal. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2002; 99: 15524-15529.
15. Gramantieri L, Ferracin M, Fornari F etal. Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res 2007; 67: 6092-6099.
16. Wong QW, Lung RW, Law PT etal. MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1. Gastroenterology 2008; 135: 257-269.
17. Varnholt H, Drebber U, Schulze F etal. MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma. Hepatology 2008; 47: 1223-1232.
18. Huang XH, Wang Q, Chen JS etal. Bead-based microarray analysis of microRNA expression in hepatocellular carcinoma: miR-338 is downregulated. Hepatol Res 2009; 39: 786-794.
19. Murakami Y, Yasuda T, Saigo K etal. Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene 2006; 25: 2537-2545.
20. Wang XW, Heegaard NH, Micro OH. RNAs in liver disease. Gastroenterology 2012; 142: 1431-1443.
21. Kim VN, Han J, Siomi MC. Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 2009; 10: 126-139.
22. Cai X, Hagedorn CH, Cullen BR. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 2004; 10: 1957-1966.
23. Gregory RI, Yan KP, Amuthan G etal. The Microprocessor complex mediates the genesis of microRNAs. Nature 2004; 432: 235-240.
24. Okada C, Yamashita E, Lee SJ etal. A high-resolution structure of the pre-microRNA nuclear export machinery. Science 2009; 326: 1275-1279.
25. Chendrimada TP, Gregory RI, Kumaraswamy E etal. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 2005; 436: 740-744.
26. Kim Y, Kim VN. MicroRNA factory: RISC assembly from precursor microRNAs. Mol Cell 2012; 46: 384-386.
27. Ender C, Krek A, Friedlander MR etal. A human snoRNA with microRNA-like functions. Mol Cell 2008; 32: 519-528.
28. Cole C, Sobala A, Lu C etal. Filtering of deep sequencing data reveals the existence of abundant Dicer-dependent small RNAs derived from tRNAs. RNA 2009; 15: 2147-2160.
29. Babiarz JE, Ruby JG, Wang Y, Bartel DP, Blelloch R. Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor-independent, Dicer-dependent small RNAs. Genes Dev 2008; 22: 2773-2785.
30. Ruby JG, Jan CH, Bartel DP. Intronic microRNA precursors that bypass Drosha processing. Nature 2007; 448: 83-86.
31. Han J, Lee Y, Yeom KH etal. Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell 2006; 125: 887-901.
32. Okamura K, Hagen JW, Duan H, Tyler DM, Lai EC. The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell 2007; 130: 89-100.
33. Dews M, Homayouni A, Yu D etal. Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat Genet 2006; 38: 1060-1065.
34. Lujambio A, Calin GA, Villanueva A etal. A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci U S A 2008; 105: 13556-13561.
35. He L, He X, Lim LP etal. A microRNA component of the p53 tumour suppressor network. Nature 2007; 447: 1130-1134.
36. Corcoran DL, Pandit KV, Gordon B, Bhattacharjee A, Kaminski N, Benos PV. Features of mammalian microRNA promoters emerge from polymerase II chromatin immunoprecipitation data. PLoS ONE 2009; 4: e5279.
37. Bracken CP, Gregory PA, Kolesnikoff N etal. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res 2008; 68: 7846-7854.
38. Saito Y, Liang G, Egger G etal. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 2006; 9: 435-443.
39. Scott GK, Mattie MD, Berger CE, Benz SC, Benz CC. Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res 2006; 66: 1277-1281.
40. Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev 2006; 20: 2202-2207.
41. Mineno J, Okamoto S, Ando T etal. The expression profile of microRNAs in mouse embryos. Nucleic Acids Res 2006; 34: 1765-1771.
42. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-674.
43. Liu WR, Shi YH, Peng YF, Fan J. Epigenetics of hepatocellular carcinoma: a new horizon. Chin Med J (Engl) 2012; 125: 2349-2360.
44. Sun J, Lu H, Wang X, Jin H. MicroRNAs in hepatocellular carcinoma: regulation, function, and clinical implications. ScientificWorldJournal 2013; 2013: 924206.
45. Yin H, Hu M, Zhang R, Shen Z, Flatow L, You M. MicroRNA-217 promotes ethanol-induced fat accumulation in hepatocytes by down-regulating SIRT1. J Biol Chem 2012; 287: 9817-9826.
46. Vinciguerra M, Sgroi A, Veyrat-Durebex C, Rubbia-Brandt L, Buhler LH, Foti M. Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes. Hepatology 2009; 49: 1176-1184.
47. O'Connell RM, Rao DS, Chaudhuri AA etal. Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med 2008; 205: 585-594.
48. Wang B, Majumder S, Nuovo G etal. Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice. Hepatology 2009; 50: 1152-1161.
49. Liu WH, Yeh SH, Lu CC etal. MicroRNA-18a prevents estrogen receptor-alpha expression, promoting proliferation of hepatocellular carcinoma cells. Gastroenterology 2009; 136: 683-693.
50. Wang Z, Lin S, Li JJ etal. MYC protein inhibits transcription of the microRNA cluster MC-let-7a-1∼let-7d via noncanonical E-box. J Biol Chem 2011; 286: 39703-39714.
51. Au SL, Wong CC, Lee JM etal. Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis. Hepatology 2012; 56: 622-631.
52. Ladeiro Y, Couchy G, Balabaud C etal. MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology 2008; 47: 1955-1963.
53. Choudhury M, Shukla SD. Surrogate alcohols and their metabolites modify histone H3 acetylation: involvement of histone acetyl transferase and histone deacetylase. Alcohol Clin Exp Res 2008; 32: 829-839.
54. Tomita K, Teratani T, Suzuki T etal. Free cholesterol accumulation in hepatic stellate cells: mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatology 2014; 59: 154-169.
55. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012; 142: 1264-1273.
56. Liu WH, Yeh SH, Chen PJ. Role of microRNAs in hepatitis B virus replication and pathogenesis. Biochim Biophys Acta 2011; 1809: 678-685.
57. Ura S, Honda M, Yamashita T etal. Differential microRNA expression between hepatitis B and hepatitis C leading disease progression to hepatocellular carcinoma. Hepatology 2009; 49: 1098-1112.
58. Ji J, Shi J, Budhu A etal. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med 2009; 361: 1437-1447.
59. Mizuguchi Y, Mishima T, Yokomuro S etal. Sequencing and bioinformatics-based analyses of the microRNA transcriptome in hepatitis B-related hepatocellular carcinoma. PLoS ONE 2011; 6: e15304.
60. Hou W, Tian Q, Zheng J, Bonkovsky HL. MicroRNA-196 represses Bach1 protein and hepatitis C virus gene expression in human hepatoma cells expressing hepatitis C viral proteins. Hepatology 2010; 51: 1494-1504.
61. Diaz G, Melis M, Tice A etal. Identification of microRNAs specifically expressed in hepatitis C virus-associated hepatocellular carcinoma. Int J Cancer 2013; 133: 816-824.
62. Chen JS, Wang Q, Fu XH etal. Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: association with MMP-9. Hepatol Res 2009; 39: 177-186.
63. Hsu HC, Tseng HJ, Lai PL, Lee PH, Peng SY. Expression of p53 gene in 184 unifocal hepatocellular carcinomas: association with tumor growth and invasiveness. Cancer Res 1993; 53: 4691-4694.
64. Bae JS, Kim JH, Pasaje CF etal. Association study of genetic variations in microRNAs with the risk of hepatitis B-related liver diseases. Dig Liver Dis 2012; 44: 849-854.
65. Xu Y, Liu L, Liu J etal. A potentially functional polymorphism in the promoter region of miR-34b/c is associated with an increased risk for primary hepatocellular carcinoma. Int J Cancer 2011; 128: 412-417.
66. Liu Y, Zhang Y, Wen J etal. A genetic variant in the promoter region of miR-106b-25 cluster and risk of HBV infection and hepatocellular carcinoma. PLoS ONE 2012; 7: e32230.
67. Kwak MS, Lee DH, Cho Y etal. Association of polymorphism in pri-microRNAs-371-372-373 with the occurrence of hepatocellular carcinoma in hepatitis B virus infected patients. PLoS ONE 2012; 7: e41983.
68. Kim WH, Min KT, Jeon YJ etal. Association study of microRNA polymorphisms with hepatocellular carcinoma in Korean population. Gene 2012; 504: 92-97.
69. Akkiz H, Bayram S, Bekar A, Akgollu E, Uskudar O. Genetic variation in the microRNA-499 gene and hepatocellular carcinoma risk in a Turkish population: lack of any association in a case-control study. Asian Pac J Cancer Prev 2011; 12: 3107-3112.
70. Xiang Y, Fan S, Cao J, Huang S, Zhang LP. Association of the microRNA-499 variants with susceptibility to hepatocellular carcinoma in a Chinese population. Mol Biol Rep 2012; 39: 7019-7023.
71. Guo J, Jin M, Zhang M, Chen K. A genetic variant in miR-196a2 increased digestive system cancer risks: a meta-analysis of 15 case-control studies. PLoS ONE 2012; 7: e30585.
72. Li XD, Li ZG, Song XX, Liu CF. A variant in microRNA-196a2 is associated with susceptibility to hepatocellular carcinoma in Chinese patients with cirrhosis. Pathology 2010; 42: 669-673.
73. Akkiz H, Bayram S, Bekar A, Akgollu E, Ulger Y. A functional polymorphism in pre-microRNA-196a-2 contributes to the susceptibility of hepatocellular carcinoma in a Turkish population: a case-control study. J Viral Hepat 2011; 18: e399-407.
74. Ji J, Zhao L, Budhu A etal. Let-7g targets collagen type I alpha2 and inhibits cell migration in hepatocellular carcinoma. J Hepatol 2010; 52: 690-697.
75. Zhang J, Yang Y, Yang T etal. microRNA-22, downregulated in hepatocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity. Br J Cancer 2010; 103: 1215-1220.
76. Xiong Y, Fang JH, Yun JP etal. Effects of microRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma. Hepatology 2010; 51: 836-845.
77. Li D, Liu X, Lin L etal. MicroRNA-99a inhibits hepatocellular carcinoma growth and correlates with prognosis of patients with hepatocellular carcinoma. J Biol Chem 2011; 286: 36677-36685.
78. Coulouarn C, Factor VM, Andersen JB, Durkin ME, Thorgeirsson SS. Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties. Oncogene 2009; 28: 3526-3536.
79. Zheng F, Liao YJ, Cai MY etal. The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut 2012; 61: 278-289.
80. Wong CC, Wong CM, Tung EK etal. The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2. Gastroenterology 2011; 140: 322-331.
81. Jia Y, Liu H, Zhuang Q etal. Tumorigenicity of cancer stem-like cells derived from hepatocarcinoma is regulated by microRNA-145. Oncol Rep 2012; 27: 1865-1872.
82. Wang C, Song B, Song W etal. Underexpressed microRNA-199b-5p targets hypoxia-inducible factor-1alpha in hepatocellular carcinoma and predicts prognosis of hepatocellular carcinoma patients. J Gastroenterol Hepatol 2011; 26: 1630-1637.
83. Wang Y, Lu Y, Toh ST etal. Lethal-7 is down-regulated by the hepatitis B virus x protein and targets signal transducer and activator of transcription 3. J Hepatol 2010; 53: 57-66.
84. Tsang WP, Kwok TT. Let-7a microRNA suppresses therapeutics-induced cancer cell death by targeting caspase-3. Apoptosis 2008; 13: 1215-1222.
85. Di Fazio P, Montalbano R, Neureiter D etal. Downregulation of HMGA2 by the pan-deacetylase inhibitor panobinostat is dependent on hsa-let-7b expression in liver cancer cell lines. Exp Cell Res 2012; 318: 1832-1843.
86. Zhu XM, Wu LJ, Xu J, Yang R, Wu FS. Let-7c microRNA expression and clinical significance in hepatocellular carcinoma. J Int Med Res 2011; 39: 2323-2329.
87. Shah YM, Morimura K, Yang Q, Tanabe T, Takagi M, Gonzalez FJ. Peroxisome proliferator-activated receptor alpha regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation. Mol Cell Biol 2007; 27: 4238-4247.
88. Shimizu S, Takehara T, Hikita H etal. The let-7 family of microRNAs inhibits Bcl-xL expression and potentiates sorafenib-induced apoptosis in human hepatocellular carcinoma. J Hepatol 2010; 52: 698-704.
89. Lan FF, Wang H, Chen YC etal. Hsa-let-7g inhibits proliferation of hepatocellular carcinoma cells by downregulation of c-Myc and upregulation of p16(INK4A). Int J Cancer 2011; 128: 319-331.
90. Li D, Yang P, Li H etal. MicroRNA-1 inhibits proliferation of hepatocarcinoma cells by targeting endothelin-1. Life Sci 2012; 91: 440-447.
91. Fang Y, Xue JL, Shen Q, Chen J, Tian L. MicroRNA-7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3-kinase/Akt pathway in hepatocellular carcinoma. Hepatology 2012; 55: 1852-1862.
92. Yan Y, Luo YC, Wan HY etal. MicroRNA-10a is involved in the metastatic process by regulating Eph tyrosine kinase receptor A4-mediated epithelial-mesenchymal transition and adhesion in hepatoma cells. Hepatology 2013; 57: 667-677.
93. Maurel M, Jalvy S, Ladeiro Y etal. A functional screening identifies five microRNAs controlling glypican-3: role of miR-1271 down-regulation in hepatocellular carcinoma. Hepatology 2013; 57: 195-204.
94. Wang Y, Jiang L, Ji X, Yang B, Zhang Y, Fu XD. Hepatitis B viral RNA directly mediates down-regulation of the tumor suppressor microRNA miR-15a/miR-16-1 in hepatocytes. J Biol Chem 2013; 288: 18484-18493.
95. Zhu Y, Lu Y, Zhang Q etal. MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein. Nucleic Acids Res 2012; 40: 4615-4625.
96. Yang X, Liang L, Zhang XF etal. MicroRNA-26a suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting interleukin-6-Stat3 pathway. Hepatology 2013; 58: 158-170.
97. Kota J, Chivukula RR, O'Donnell KA etal. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 2009; 137: 1005-1017.
98. Zhu XC, Dong QZ, Zhang XF etal. microRNA-29a suppresses cell proliferation by targeting SPARC in hepatocellular carcinoma. Int J Mol Med 2012; 30: 1321-1326.
99. Fang JH, Zhou HC, Zeng C etal. MicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression. Hepatology 2011; 54: 1729-1740.
100. Bae HJ, Noh JH, Kim JK etal. MicroRNA-29c functions as a tumor suppressor by direct targeting oncogenic SIRT1 in hepatocellular carcinoma. Oncogene 2014; 33: 2557-2567.
101. Li N, Fu H, Tie Y etal. miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer Lett 2009; 275: 44-53.
102. Yang P, Li QJ, Feng Y etal. TGF-beta-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell 2012; 22: 291-303.
103. Petrelli A, Perra A, Schernhuber K etal. Sequential analysis of multistage hepatocarcinogenesis reveals that miR-100 and PLK1 dysregulation is an early event maintained along tumor progression. Oncogene 2012; 31: 4517-4526.
104. Wang L, Zhang X, Jia LT etal. c-Myc-mediated epigenetic silencing of MicroRNA-101 contributes to dysregulation of multiple pathways in hepatocellular carcinoma. Hepatology 2014; 59: 1850-1863.
105. Su H, Yang JR, Xu T etal. MicroRNA-101, down-regulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity. Cancer Res 2009; 69: 1135-1142.
106. Li S, Fu H, Wang Y etal. MicroRNA-101 regulates expression of the v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS) oncogene in human hepatocellular carcinoma. Hepatology 2009; 49: 1194-1202.
107. Lin CJ, Gong HY, Tseng HC, Wang WL, Wu JL. miR-122 targets an anti-apoptotic gene, Bcl-w, in human hepatocellular carcinoma cell lines. Biochem Biophys Res Commun 2008; 375: 315-320.
108. Kong G, Zhang J, Zhang S, Shan C, Ye L, Zhang X. Upregulated microRNA-29a by hepatitis B virus X protein enhances hepatoma cell migration by targeting PTEN in cell culture model. PLoS ONE 2011; 6: e19518.
109. Reddi HV, Madde P, Milosevic D etal. The putative PAX8/PPARgamma fusion oncoprotein exhibits partial tumor suppressor activity through up-regulation of micro-RNA-122 and dominant-negative PPARgamma activity. Genes Cancer 2011; 2: 46-55.
110. Xu J, Zhu X, Wu L etal. MicroRNA-122 suppresses cell proliferation and induces cell apoptosis in hepatocellular carcinoma by directly targeting Wnt/beta-catenin pathway. Liver Int 2012; 32: 752-760.
111. Lang Q, Ling C. MiR-124 suppresses cell proliferation in hepatocellular carcinoma by targeting PIK3CA. Biochem Biophys Res Commun 2012; 426: 247-252.
112. Bi Q, Tang S, Xia L etal. Ectopic expression of MiR-125a inhibits the proliferation and metastasis of hepatocellular carcinoma by targeting MMP11 and VEGF. PLoS ONE 2012; 7: e40169.
113. Kim JK, Noh JH, Jung KH etal. Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b. Hepatology 2013; 57: 1055-1067.
114. Zhao A, Zeng Q, Xie X etal. MicroRNA-125b induces cancer cell apoptosis through suppression of Bcl-2 expression. J Genet Genomics 2012; 39: 29-35.
115. Alpini G, Glaser SS, Zhang JP etal. Regulation of placenta growth factor by microRNA-125b in hepatocellular cancer. J Hepatol 2011; 55: 1339-1345.
116. Liang L, Wong CM, Ying Q etal. MicroRNA-125b suppressesed human liver cancer cell proliferation and metastasis by directly targeting oncogene LIN28B2. Hepatology 2010; 52: 1731-1740.
117. Fan DN, Tsang FH, Tam AH etal. Histone lysine methyltransferase, suppressor of variegation 3-9 homolog 1, promotes hepatocellular carcinoma progression and is negatively regulated by microRNA-125b. Hepatology 2013; 57: 637-647.
118. Wong QW, Ching AK, Chan AW etal. MiR-222 overexpression confers cell migratory advantages in hepatocellular carcinoma through enhancing AKT signaling. Clin Cancer Res 2010; 16: 867-875.
119. Fan Q, He M, Deng X etal. Derepression of c-Fos caused by microRNA-139 down-regulation contributes to the metastasis of human hepatocellular carcinoma. Cell Biochem Funct 2013; 31: 319-324.
120. Yang H, Fang F, Chang R, Yang L. MicroRNA-140-5p suppresses tumor growth and metastasis by targeting transforming growth factor beta receptor 1 and fibroblast growth factor 9 in hepatocellular carcinoma. Hepatology 2013; 58: 205-217.
121. Takata A, Otsuka M, Yoshikawa T etal. MicroRNA-140 acts as a liver tumor suppressor by controlling NF-kappaB activity by directly targeting DNA methyltransferase 1 (Dnmt1) expression. Hepatology 2013; 57: 162-170.
122. Banaudha K, Kaliszewski M, Korolnek T etal. MicroRNA silencing of tumor suppressor DLC-1 promotes efficient hepatitis C virus replication in primary human hepatocytes. Hepatology 2011; 53: 53-61.
123. Law PT, Ching AK, Chan AW etal. MiR-145 modulates multiple components of the insulin-like growth factor pathway in hepatocellular carcinoma. Carcinogenesis 2012; 33: 1134-1141.
124. Gailhouste L, Gomez-Santos L, Hagiwara K etal. miR-148a plays a pivotal role in the liver by promoting the hepatospecific phenotype and suppressing the invasiveness of transformed cells. Hepatology 2013; 58: 1153-1165.
125. Xu X, Fan Z, Kang L etal. Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis. J Clin Invest 2013; 123: 630-645.
126. Zhang JP, Zeng C, Xu L, Gong J, Fang JH, Zhuang SM. MicroRNA-148a suppresses the epithelial-mesenchymal transition and metastasis of hepatoma cells by targeting Met/Snail signaling. Oncogene 2013; [Epub ahead of print].
127. Han H, Sun D, Li W etal. A c-Myc-MicroRNA functional feedback loop affects hepatocarcinogenesis. Hepatology 2013; 57: 2378-2389.
128. Huang J, Wang Y, Guo Y, Sun S. Down-regulated microRNA-152 induces aberrant DNA methylation in hepatitis B virus-related hepatocellular carcinoma by targeting DNA methyltransferase 1. Hepatology 2010; 52: 60-70.
129. Xu T, Zhu Y, Xiong Y, Ge YY, Yun JP, Zhuang SM. MicroRNA-195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells. Hepatology 2009; 50: 113-121.
130. Yang X, Yu J, Yin J, Xiang Q, Tang H, Lei X. MiR-195 regulates cell apoptosis of human hepatocellular carcinoma cells by targeting LATS2. Pharmazie 2012; 67: 645-651.
131. Fornari F, Milazzo M, Chieco P etal. MiR-199a-3p regulates mTOR and c-Met to influence the doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res 2010; 70: 5184-5193.
132. Hou J, Lin L, Zhou W etal. Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma. Cancer Cell 2011; 19: 232-243.
133. Shatseva T, Lee DY, Deng Z, Yang BB. MicroRNA miR-199a-3p regulates cell proliferation and survival by targeting caveolin-2. J Cell Sci 2011; 124: 2826-2836.
134. Shen Q, Cicinnati VR, Zhang X etal. Role of microRNA-199a-5p and discoidin domain receptor 1 in human hepatocellular carcinoma invasion. Mol Cancer 2010; 9: 227.
135. Xu N, Zhang J, Shen C etal. Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell. Biochem Biophys Res Commun 2012; 423: 826-831.
136. Gao P, Wong CC, Tung EK, Lee JM, Wong CM, Ng IO. Deregulation of microRNA expression occurs early and accumulates in early stages of HBV-associated multistep hepatocarcinogenesis. J Hepatol 2011; 54: 1177-1184.
137. Yuan JH, Yang F, Chen BF etal. The histone deacetylase 4/SP1/microrna-200a regulatory network contributes to aberrant histone acetylation in hepatocellular carcinoma. Hepatology 2011; 54: 2025-2035.
138. Wei W, Wanjun L, Hui S, Dongyue C, Xinjun Y, Jisheng Z. miR-203 inhibits proliferation of HCC cells by targeting survivin. Cell Biochem Funct 2013; 31: 82-85.
139. Shih TC, Tien YJ, Wen CJ etal. MicroRNA-214 downregulation contributes to tumor angiogenesis by inducing secretion of the hepatoma-derived growth factor in human hepatoma. J Hepatol 2012; 57: 584-591.
140. Wang X, Chen J, Li F etal. MiR-214 inhibits cell growth in hepatocellular carcinoma through suppression of beta-catenin. Biochem Biophys Res Commun 2012; 428: 525-531.
141. Xia H, Ooi LL, Hui KM. MiR-214 targets beta-catenin pathway to suppress invasion, stem-like traits and recurrence of human hepatocellular carcinoma. PLoS ONE 2012; 7: e44206.
142. Huang N, Lin J, Ruan J etal. MiR-219-5p inhibits hepatocellular carcinoma cell proliferation by targeting glypican-3. FEBS Lett 2012; 586: 884-891.
143. Guichard C, Amaddeo G, Imbeaud S etal. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet 2012; 44: 694-698.
144. Chang Y, Yan W, He X etal. miR-375 inhibits autophagy and reduces viability of hepatocellular carcinoma cells under hypoxic conditions. Gastroenterology 2012; 143: 177-187.
145. He XX, Chang Y, Meng FY etal. MicroRNA-375 targets AEG-1 in hepatocellular carcinoma and suppresses liver cancer cell growth in vitro and in vivo. Oncogene 2012; 31: 3357-3369.
146. Zheng Y, Yin L, Chen H etal. miR-376a suppresses proliferation and induces apoptosis in hepatocellular carcinoma. FEBS Lett 2012; 586: 2396-2403.
147. You X, Liu F, Zhang T, Li Y, Ye L, Zhang X. Hepatitis B virus X protein upregulates oncogene Rab18 to result in the dysregulation of lipogenesis and proliferation of hepatoma cells. Carcinogenesis 2013; 34: 1644-1652.
148. Buurman R, Gurlevik E, Schaffer V etal. Histone deacetylases activate hepatocyte growth factor signaling by repressing microRNA-449 in hepatocellular carcinoma cells. Gastroenterology 2012; 143: 811-820. e1-15.
149. Weng Z, Wang D, Zhao W etal. microRNA-450a targets DNA methyltransferase 3a in hepatocellular carcinoma. Exp Ther Med 2011; 2: 951-955.
150. Zhang W, Kong G, Zhang J, Wang T, Ye L, Zhang X. MicroRNA-520b inhibits growth of hepatoma cells by targeting MEKK2 and cyclin D1. PLoS ONE 2012; 7: e31450.
151. Zhang S, Shan C, Kong G, Du Y, Ye L, Zhang X. MicroRNA-520e suppresses growth of hepatoma cells by targeting the NF-kappaB-inducing kinase (NIK). Oncogene 2012; 31: 3607-3620.
152. Tao ZH, Wan JL, Zeng LY etal. miR-612 suppresses the invasive-metastatic cascade in hepatocellular carcinoma. J Exp Med 2013; 210: 789-803.
153. Zhang JF, He ML, Fu WM etal. Primate-specific microRNA-637 inhibits tumorigenesis in hepatocellular carcinoma by disrupting signal transducer and activator of transcription 3 signaling. Hepatology 2011; 54: 2137-2148.
154. Li QJ, Zhou L, Yang F etal. MicroRNA-10b promotes migration and invasion through CADM1 in human hepatocellular carcinoma cells. Tumour Biol 2012; 33: 1455-1465.
155. Chen L, Jiang M, Yuan W, Tang H. miR-17-5p as a novel prognostic marker for hepatocellular carcinoma. J Invest Surg 2012; 25: 156-161.
156. Karakatsanis A, Papaconstantinou I, Gazouli M, Lyberopoulou A, Polymeneas G, Voros D. Expression of microRNAs, miR-21, miR-31, miR-122, miR-145, miR-146a, miR-200c, miR-221, miR-222, and miR-223 in patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma and its prognostic significance. Mol Carcinog 2013; 52: 297-303.
157. Liu S, Guo W, Shi J etal. MicroRNA-135a contributes to the development of portal vein tumor thrombus by promoting metastasis in hepatocellular carcinoma. J Hepatol 2012; 56: 389-396.
158. Han ZB, Chen HY, Fan JW, Wu JY, Tang HM, Peng ZH. Up-regulation of microRNA-155 promotes cancer cell invasion and predicts poor survival of hepatocellular carcinoma following liver transplantation. J Cancer Res Clin Oncol 2012; 138: 153-161.
159. Wang J, Li J, Shen J, Wang C, Yang L, Zhang X. MicroRNA-182 downregulates metastasis suppressor 1 and contributes to metastasis of hepatocellular carcinoma. BMC Cancer 2012; 12: 227.
160. Yang F, Yin Y, Wang F etal. miR-17-5p Promotes migration of human hepatocellular carcinoma cells through the p38 mitogen-activated protein kinase-heat shock protein 27 pathway. Hepatology 2010; 51: 1614-1623.
161. Jiang R, Deng L, Zhao L etal. miR-22 promotes HBV-related hepatocellular carcinoma development in males. Clin Cancer Res 2011; 17: 5593-5603.
162. Wang B, Hsu SH, Frankel W, Ghoshal K, Jacob ST. Stat3-mediated activation of microRNA-23a suppresses gluconeogenesis in hepatocellular carcinoma by down-regulating glucose-6-phosphatase and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha. Hepatology 2012; 56: 186-197.
163. Yao J, Liang L, Huang S etal. MicroRNA-30d promotes tumor invasion and metastasis by targeting Galphai2 in hepatocellular carcinoma. Hepatology 2010; 51: 846-856.
164. Shen G, Jia H, Tai Q, Li Y, Chen D. miR-106b downregulates adenomatous polyposis coli and promotes cell proliferation in human hepatocellular carcinoma. Carcinogenesis 2013; 34: 211-219.
165. Ma S, Tang KH, Chan YP etal. miR-130b Promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell 2010; 7: 694-707.
166. Zhang X, Liu S, Hu T, Liu S, He Y, Up-regulated SS. microRNA-143 transcribed by nuclear factor kappa B enhances hepatocarcinoma metastasis by repressing fibronectin expression. Hepatology 2009; 50: 490-499.
167. Luedde T. MicroRNA-151 and its hosting gene FAK (focal adhesion kinase) regulate tumor cell migration and spreading of hepatocellular carcinoma. Hepatology 2010; 52: 1164-1166.
168. Ding J, Huang S, Wu S etal. Gain of miR-151 on chromosome 8q24.3 facilitates tumour cell migration and spreading through downregulating RhoGDIA. Nat Cell Biol 2010; 12: 390-399.
169. Zhang Y, Wei W, Cheng N etal. Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling. Hepatology 2012; 56: 1631-1640.
170. Yan XL, Jia YL, Chen L etal. Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: role of the S100A4-miR155-SOCS1-MMP9 axis. Hepatology 2013; 57: 2274-2286.
171. Wang B, Hsu SH, Majumder S etal. TGFbeta-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3. Oncogene 2010; 29: 1787-1797.
172. Goeppert B, Schmezer P, Dutruel C etal. Down-regulation of tumor suppressor A kinase anchor protein 12 in human hepatocarcinogenesis by epigenetic mechanisms. Hepatology 2010; 52: 2023-2033.
173. Petrelli A, Perra A, Cora D etal. MicroRNA/gene profiling unveils early molecular changes and nuclear factor erythroid related factor 2 (NRF2) activation in a rat model recapitulating human hepatocellular carcinoma (HCC). Hepatology 2014; 59: 228-241.
174. Ying Q, Liang L, Guo W etal. Hypoxia-inducible microRNA-210 augments the metastatic potential of tumor cells by targeting vacuole membrane protein 1 in hepatocellular carcinoma. Hepatology 2011; 54: 2064-2075.
175. Chen PJ, Yeh SH, Liu WH etal. Androgen pathway stimulates microRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis. Hepatology 2012; 56: 632-643.
176. Xia H, Ooi LL, Hui KM. MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer. Hepatology 2013; 58: 629-641.
177. Callegari E, Elamin BK, Giannone F etal. Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model. Hepatology 2012; 56: 1025-1033.
178. Yuan Q, Loya K, Rani B etal. MicroRNA-221 overexpression accelerates hepatocyte proliferation during liver regeneration. Hepatology 2013; 57: 299-310.
179. Gramantieri L, Fornari F, Ferracin M etal. MicroRNA-221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality. Clin Cancer Res 2009; 15: 5073-5081.
180. Pineau P, Volinia S, McJunkin K etal. miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci U S A 2010; 107: 264-269.
181. Lan SH, Wu SY, Zuchini R etal. Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of microRNA-224. Hepatology 2014; 59: 505-517.
182. Scisciani C, Vossio S, Guerrieri F etal. Transcriptional regulation of miR-224 upregulated in human HCCs by NFkappaB inflammatory pathways. J Hepatol 2012; 56: 855-861.
183. Zhou P, Jiang W, Wu L, Chang R, Wu K, Wang Z. miR-301a is a candidate oncogene that targets the homeobox gene Gax in human hepatocellular carcinoma. Dig Dis Sci 2012; 57: 1171-1180.
184. Wu N, Liu X, Xu X etal. MicroRNA-373, a new regulator of protein phosphatase 6, functions as an oncogene in hepatocellular carcinoma. FEBS J 2011; 278: 2044-2054.
185. Lin J, Huang S, Wu S etal. MicroRNA-423 promotes cell growth and regulates G(1)/S transition by targeting p21Cip1/Waf1 in hepatocellular carcinoma. Carcinogenesis 2011; 32: 1641-1647.
186. Yang H, Cho ME, Li TW etal. MicroRNAs regulate methionine adenosyltransferase 1A expression in hepatocellular carcinoma. J Clin Invest 2013; 123: 285-298.
187. Zhang LY, Liu M, Li X, Tang H. miR-490-3p modulates cell growth and epithelial to mesenchymal transition of hepatocellular carcinoma cells by targeting endoplasmic reticulum-Golgi intermediate compartment protein 3 (ERGIC3). J Biol Chem 2013; 288: 4035-4047.
188. Lim L, Balakrishnan A, Huskey N etal. MicroRNA-494 within an oncogenic microRNA megacluster regulates G1/S transition in liver tumorigenesis through suppression of mutated in colorectal cancer. Hepatology 2014; 59: 202-215.
189. Toffanin S, Hoshida Y, Lachenmayer A etal. MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a. Gastroenterology 2011; 140: 1618-1628. e16.
190. Fornari F, Milazzo M, Chieco P etal. In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2. J Pathol 2012; 227: 275-285.
191. Tian Q, Liang L, Ding J etal. MicroRNA-550a acts as a pro-metastatic gene and directly targets cytoplasmic polyadenylation element-binding protein 4 in hepatocellular carcinoma. PLoS ONE 2012; 7: e48958.
192. Jiang X, Xiang G, Wang Y etal. MicroRNA-590-5p regulates proliferation and invasion in human hepatocellular carcinoma cells by targeting TGF-beta RII. Mol Cells 2012; 33: 545-551.
193. El Tayebi HM, Hosny KA, Esmat G, Breuhahn K, Abdelaziz AI. miR-615-5p is restrictedly expressed in cirrhotic and cancerous liver tissues and its overexpression alleviates the tumorigenic effects in hepatocellular carcinoma. FEBS Lett 2012; 586: 3309-3316.
194. Zhang L, Yang L, Liu X etal. MicroRNA-657 promotes tumorigenesis in hepatocellular carcinoma by targeting transducin-like enhancer protein 1 through nuclear factor kappa B pathways. Hepatology 2013; 57: 1919-1930.
195. Law PT, Qin H, Ching AK etal. Deep sequencing of small RNA transcriptome reveals novel non-coding RNAs in hepatocellular carcinoma. J Hepatol 2013; 58: 1165-1173.
196. Yamamoto Y, Kosaka N, Tanaka M etal. MicroRNA-500 as a potential diagnostic marker for hepatocellular carcinoma. Biomarkers 2009; 14: 529-538.
197. Li LM, Hu ZB, Zhou ZX etal. Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Res 2010; 70: 9798-9807.
198. Tsai WC, Hsu PW, Lai TC etal. MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma. Hepatology 2009; 49: 1571-1582.
199. Park JK, Kogure T, Nuovo GJ etal. miR-221 silencing blocks hepatocellular carcinoma and promotes survival. Cancer Res 2011; 71: 7608-7616.
200. Kato K, Gong J, Iwama H etal. The antidiabetic drug metformin inhibits gastric cancer cell proliferation in vitro and in vivo. Mol Cancer Ther 2012; 11: 549-560.
201. Kobayashi M, Kato K, Iwama H etal. Antitumor effect of metformin in esophageal cancer: in vitro study. Int J Oncol 2013; 42: 517-524.
202. Miyoshi H, Kato K, Iwama H etal. Effect of the anti-diabetic drug metformin in hepatocellular carcinoma in vitro and in vivo. Int J Oncol 2014; 45: 322-332.
203. Tomimaru Y, Eguchi H, Nagano H etal. MicroRNA-21 induces resistance to the anti-tumour effect of interferon-alpha/5-fluorouracil in hepatocellular carcinoma cells. Br J Cancer 2010; 103: 1617-1626.