1. Liver Transplantation Center of the First Affiliated Hospital and Cancer Center, Nanjing Medical University, Nanjing 210029, China; 2. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology, Cancer Center, UCSD School of Medicine, La Jolla, CA 92093-0723, USA
Inflammation has been considered as one of the hallmarks of cancer, and chronic hepatitis is a major cause of liver cancer. This review will focus on the pathogenic role of inflammation in hepatocarcinogenesis and will discuss recent advances in understanding the chronic hepatitis-liver cancer link based on hot spots in liver cancer research, including cellular interaction, cytokines, microRNA and stem cells. All of these mechanisms should be taken into consideration because they are crucial for the development of more efficacious therapeutic strategies for preventing and treating human chronic hepatitis and hepatocellular carcinoma.
Corresponding Author(s):
Sun Beicheng,Email:sunbc@njmu.edu.cn; Karin Michael,Email:karinoffice@ucsd.edu
引用本文:
. Inflammation and liver tumorigenesis[J]. Frontiers of Medicine, 2013, 7(2): 242-254.
Beicheng Sun, Michael Karin. Inflammation and liver tumorigenesis. Front Med, 2013, 7(2): 242-254.
Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008; 27(45): 5904-5912 doi: 10.1038/onc.2008.271 pmid:18836471
2
Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A, Gupta S, Moore J, Wrobel MJ, Lerner J, Reich M, Chan JA, Glickman JN, Ikeda K, Hashimoto M, Watanabe G, Daidone MG, Roayaie S, Schwartz M, Thung S, Salvesen HB, Gabriel S, Mazzaferro V, Bruix J, Friedman SL, Kumada H, Llovet JM, Golub TR. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 2008; 359(19): 1995-2004 doi: 10.1056/NEJMoa0804525 pmid:18923165
3
Levrero M. Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene 2006; 25(27): 3834-3847 doi: 10.1038/sj.onc.1209562 pmid:16799625
4
Sweet MJ, Hume DA. Endotoxin signal transduction in macrophages. J Leukoc Biol 1996; 60(1): 8-26 pmid:8699127
5
Yan S, Wang L, Liu N, Wang Y, Chu Y. Critical role of interleukin-17/interleukin-17 receptor axis in mediating Con A-induced hepatitis. Immunol Cell Biol 2012; 90(4): 421-428 pmid:21691280
6
Hsieh WT, Tsai CT, Wu JB, Hsiao HB, Yang LC, Lin WC. Kinsenoside, a high yielding constituent from Anoectochilus formosanus, inhibits carbon tetrachloride induced Kupffer cells mediated liver damage. J Ethnopharmacol 2011; 135(2): 440-449 doi: 10.1016/j.jep.2011.03.040 pmid:21470577
7
Ramaiah SK, Jaeschke H. Role of neutrophils in the pathogenesis of acute inflammatory liver injury. Toxicol Pathol 2007; 35(6): 757-766 doi: 10.1080/01926230701584163 pmid:17943649
8
Jaeschke H, Hasegawa T. Role of neutrophils in acute inflammatory liver injury. Liver Int 2006; 26(8): 912-919 doi: 10.1111/j.1478-3231.2006.01327.x pmid:16953830
9
Jaeschke H, Farhood A. Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver. Am J Physiol 1991; 260(3 Pt 1): G355-G362 pmid:2003603
10
Lee WM. Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure. Hepatology 2004; 40(1): 6-9 doi: 10.1002/hep.20293 pmid:15239078
11
Knolle PA, Gerken G. Local control of the immune response in the liver. Immunol Rev 2000;174:21-34 pmid:10807504
12
Ishida Y, Kondo T, Ohshima T, Fujiwara H, Iwakura Y, Mukaida N. A pivotal involvement of IFN-gamma in the pathogenesis of acetaminophen-induced acute liver injury. FASEB J 2002; 16(10): 1227-1236 doi: 10.1096/fj.02-0046com pmid:12153990
13
Liu ZX, Govindarajan S, Kaplowitz N. Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Gastroenterology 2004; 127(6): 1760-1774 doi: 10.1053/j.gastro.2004.08.053 pmid:15578514
14
Arshad MI, Rauch M, L’helgoualc’h A, Julia V, Leite-de-Moraes MC, Lucas-Clerc C, Piquet-Pellorce C, Samson M. NKT cells are required to induce high IL-33 expression in hepatocytes during ConA-induced acute hepatitis. Eur J Immunol 2011; 41(8): 2341-2348 doi: 10.1002/eji.201041332 pmid:21557213
15
Bissell DM, Wang SS, Jarnagin WR, Roll FJ. Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation. J Clin Invest 1995; 96(1): 447-455 doi: 10.1172/JCI118055 pmid:7615817
16
Knolle PA, L?ser E, Protzer U, Duchmann R, Schmitt E, zum Büschenfelde KH, Rose-John S, Gerken G. Regulation of endotoxin-induced IL-6 production in liver sinusoidal endothelial cells and Kupffer cells by IL-10. Clin Exp Immunol 1997; 107(3): 555-561 doi: 10.1046/j.1365-2249.1997.d01-959.x pmid:9067532
17
Knolle PA, Germann T, Treichel U, Uhrig A, Schmitt E, Hegenbarth S, Lohse AW, Gerken G. Endotoxin down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells. J Immunol 1999; 162(3): 1401-1407 pmid:9973395
18
Knolle PA, Limmer A. Neighborhood politics: the immunoregulatory function of organ-resident liver endothelial cells. Trends Immunol 2001; 22(8): 432-437 doi: 10.1016/S1471-4906(01)01957-3 pmid:11473832
19
Knolle PA, Uhrig A, Hegenbarth S, L?ser E, Schmitt E, Gerken G, Lohse AW. IL-10 down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells through decreased antigen uptake via the mannose receptor and lowered surface expression of accessory molecules. Clin Exp Immunol 1998; 114(3): 427-433 doi: 10.1046/j.1365-2249.1998.00713.x pmid:9844054
20
Crispe IN. The liver as a lymphoid organ. Annu Rev Immunol 2009; 27: 147-163 pmid:19302037
21
Kojima N, Sato M, Suzuki A, Sato T, Satoh S, Kato T, Senoo H. Enhanced expression of B7-1, B7-2, and intercellular adhesion molecule 1 in sinusoidal endothelial cells by warm ischemia/reperfusion injury in rat liver. Hepatology 2001; 34(4): 751-757 doi: 10.1053/jhep.2001.27804 pmid:11584372
Chappell L, Kaiser P, Barrow P, Jones MA, Johnston C, Wigley P. The immunobiology of avian systemic salmonellosis. Vet Immunol Immunopathol 2009; 128(1-3): 53-59 doi: 10.1016/j.vetimm.2008.10.295 pmid:19070366
24
Larrubia JR, Benito-Martínez S, Calvino M, Sanz-de-Villalobos E, Parra-Cid T. Role of chemokines and their receptors in viral persistence and liver damage during chronic hepatitis C virus infection. World J Gastroenterol 2008; 14(47): 7149-7159 doi: 10.3748/wjg.14.7149 pmid:19084927
25
Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol 2008; 214(2): 199-210 doi: 10.1002/path.2277 pmid:18161745
26
Movahedi K, Laoui D, Gysemans C, Baeten M, Stangé G, Van den Bossche J, Mack M, Pipeleers D, In’t Veld P, De Baetselier P, Van Ginderachter JA. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 2010; 70(14): 5728-5739 doi: 10.1158/0008-5472.CAN-09-4672 pmid:20570887
27
Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 2010; 11(10): 889-896 doi: 10.1038/ni.1937 pmid:20856220
28
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010; 140(6): 883-899 doi: 10.1016/j.cell.2010.01.025 pmid:20303878
29
Karin M. Nuclear factor-kappaB in cancer development and progression. Nature 2006; 441(7092): 431-436 doi: 10.1038/nature04870 pmid:16724054
30
Zamarron BF, Chen W. Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci 2011; 7(5): 651-658 doi: 10.7150/ijbs.7.651 pmid:21647333
31
Chen S, Akbar SM, Abe M, Hiasa Y, Onji M. Immunosuppressive functions of hepatic myeloid-derived suppressor cells of normal mice and in a murine model of chronic hepatitis B virus. Clin Exp Immunol 2011; 166(1): 134-142 doi: 10.1111/j.1365-2249.2011.04445.x pmid:21762128
32
Hu CE, Gan J, Zhang RD, Cheng YR, Huang GJ. Up-regulated myeloid-derived suppressor cell contributes to hepatocellular carcinoma development by impairing dendritic cell function. Scand J Gastroenterol 2011; 46(2): 156-164 doi: 10.3109/00365521.2010.516450 pmid:20822377
33
Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Krüger C, Manns MP, Greten TF, Korangy F. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 2008; 135(1): 234-243 doi: 10.1053/j.gastro.2008.03.020 pmid:18485901
34
Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H, Lehner F, Manns MP, Greten TF, Korangy F. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 2009; 50(3): 799-807 doi: 10.1002/hep.23054 pmid:19551844
35
Grivennikov SI, Karin M. Inflammation and oncogenesis: a vicious connection. Curr Opin Genet Dev 2010; 20(1): 65-71 doi: 10.1016/j.gde.2009.11.004 pmid:20036794
36
Voloboueva LA, Giffard RG. Inflammation, mitochondria, and the inhibition of adult neurogenesis. J Neurosci Res 2011; 89(12): 1989-1996 doi: 10.1002/jnr.22768 pmid:21910136
37
Tawara K, Oxford JT, Jorcyk CL. Clinical significance of interleukin (IL)-6 in cancer metastasis to bone: potential of anti-IL-6 therapies. Cancer Manag Res 2011;3:177-189 pmid:21625400
38
Tanaka T, Narazaki M, Kishimoto T. Therapeutic Targeting of the Interleukin-6 Receptor. Annu Rev Pharmacol Toxicol 2012; 52: 199-219 pmid:21910626
39
Mair M, Blaas L, Osterreicher CH, Casanova E, Eferl R. JAK-STAT signaling in hepatic fibrosis. Front Biosci 2011; 17: 2794-2811 pmid:21622209
40
Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest 2011; 121(9): 3375-3383 doi: 10.1172/JCI57158 pmid:21881215
41
Erreni M, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) and inflammation in colorectal cancer. Cancer Microenviron 2011; 4(2): 141-154 doi: 10.1007/s12307-010-0052-5 pmid:21909876
42
Wang YC, Xu GL, Jia WD, Han SJ, Ren WH, Wang W, Liu WB, Zhang CH, Chen H. Estrogen suppresses metastasis in rat hepatocellular carcinoma through decreasing interleukin-6 and hepatocyte growth factor expression. Inflammation 2012; 35(1): 143-149 pmid:21302136
43
Jiang R, Deng L, Zhao L, Li X, Zhang F, Xia Y, Gao Y, Wang X, Sun B. miR-22 promotes HBV-related hepatocellular carcinoma development in males. Clin Cancer Res 2011; 17(17): 5593-5603 doi: 10.1158/1078-0432.CCR-10-1734 pmid:21750200
44
Hsu SH, Wang LT, Lee KT, Chen YL, Liu KY, Suen JL, Chai CY, Wang SN. Pro-inflammatory homeobox gene, ISX, regulates tumor growth and survival in hepatocellular carcinoma. Cancer Res Cancer Res 2013; 73(2): 508-518 pmid:23221382
45
Kroy DC, Beraza N, Tschaharganeh DF, Sander LE, Erschfeld S, Giebeler A, Liedtke C, Wasmuth HE, Trautwein C, Streetz KL. Lack of interleukin-6/glycoprotein 130/signal transducers and activators of transcription-3 signaling in hepatocytes predisposes to liver steatosis and injury in mice. Hepatology 2010; 51(2): 463-473 doi: 10.1002/hep.23322 pmid:19918973
46
Ando M, Uehara I, Kogure K, Asano Y, Nakajima W, Abe Y, Kawauchi K, Tanaka N. Interleukin 6 enhances glycolysis through expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3. J Nippon Med Sch 2010; 77(2): 97-105 doi: 10.1272/jnms.77.97 pmid:20453422
47
Liu Y, Li PK, Li C, Lin J. Inhibition of STAT3 signaling blocks the anti-apoptotic activity of IL-6 in human liver cancer cells. J Biol Chem 2010; 285(35): 27429-27439 doi: 10.1074/jbc.M110.142752 pmid:20562100
48
Alison MR, Nicholson LJ, Lin WR. Chronic inflammation and hepatocellular carcinoma. Recent Results Cancer Res 2011; 185: 135-148 pmid:21822824
49
Sander LE, Sackett SD, Dierssen U, Beraza N, Linke RP, Müller M, Blander JM, Tacke F, Trautwein C. Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function. J Exp Med 2010; 207(7): 1453-1464 doi: 10.1084/jem.20091474 pmid:20530204
50
Kushibiki S. Tumor necrosis factor-α-induced inflammatory responses in cattle. Anim Sci J 2011; 82(4): 504-511 doi: 10.1111/j.1740-0929.2011.00931.x pmid:21794006
51
Caminero A, Comabella M, Montalban X. Tumor necrosis factor alpha (TNF-α), anti-TNF-α and demyelination revisited: an ongoing story. J Neuroimmunol 2011; 234(1-2): 1-6 doi: 10.1016/j.jneuroim.2011.03.004 pmid:21474190
52
Shukla R, Yue J, Siouda M, Gheit T, Hantz O, Merle P, Zoulim F, Krutovskikh V, Tommasino M, Sylla BS. Proinflammatory cytokine TNF-α increases the stability of hepatitis B virus X protein through NF-κB signaling. Carcinogenesis 2011; 32(7): 978-985 doi: 10.1093/carcin/bgr057 pmid:21459755
53
Shi Z, Du C. Tumor necrosis factor alpha 308 G/A polymorphism and hepatocellular carcinoma risk in a Chinese population. Genet Test Mol Biomarkers 2011; 15(7-8): 569-572 doi: 10.1089/gtmb.2011.0008 pmid:21401328
54
Wang B, Wang J, Zheng Y, Zhou S, Zheng J, Wang F, Ma X, Zeng Z. A study of TNF-alpha-238 and-308 polymorphisms with different outcomes of persistent hepatitis B virus infection in China. Pathology 2010; 42(7): 674-680 doi: 10.3109/00313025.2010.523696 pmid:21080879
55
Chen KF, Tai WT, Liu TH, Huang HP, Lin YC, Shiau CW, Li PK, Chen PJ, Cheng AL. Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3. Clin Cancer Res 2010; 16(21): 5189-5199 doi: 10.1158/1078-0432.CCR-09-3389 pmid:20884624
56
Xia L, Mo P, Huang W, Zhang L, Wang Y, Zhu H, Tian D, Liu J, Chen Z, Zhang Y, Chen Z, Hu H, Fan D, Nie Y, Wu K. The TNF-α/ROS/HIF-1-induced upregulation of FoxMI expression promotes HCC proliferation and resistance to apoptosis. Carcinogenesis 2012; 33(11): 2250-2259 doi: 10.1093/carcin/bgs249 pmid:22831955
57
Muntané J. Targeting cell death and survival receptors in hepatocellular carcinoma. Anticancer Agents Med Chem 2011; 11(6): 576-584 doi: 10.2174/187152011796011082 pmid:21554206
58
Kriegl L, Jung A, Engel J, Jackstadt R, Gerbes AL, Gallmeier E, Reiche JA, Hermeking H, Rizzani A, Bruns CJ, Kolligs FT, Kirchner T, G?ke B, De Toni EN. Expression, cellular distribution, and prognostic relevance of TRAIL receptors in hepatocellular carcinoma. Clin Cancer Res 2010; 16(22): 5529-5538 doi: 10.1158/1078-0432.CCR-09-3403 pmid:20889918
59
Giannelli G, Mazzocca A, Fransvea E, Lahn M, Antonaci S. Inhibiting TGF-β signaling in hepatocellular carcinoma. Biochim Biophys Acta 2011; 1815(2): 214-223 pmid:21129443
60
Achyut BR, Yang L. Transforming growth factor-β in the gastrointestinal and hepatic tumor microenvironment. Gastroenterology 2011; 141(4): 1167-1178 doi: 10.1053/j.gastro.2011.07.048 pmid:21839702
Coulouarn C, Factor VM, Thorgeirsson SS. Transforming growth factor-beta gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology 2008; 47(6): 2059-2067 doi: 10.1002/hep.22283 pmid:18506891
63
Mamiya T, Yamazaki K, Masugi Y, Mori T, Effendi K, Du W, Hibi T, Tanabe M, Ueda M, Takayama T, Sakamoto M. Reduced transforming growth factor-beta receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis. Lab Invest 2010; 90(9): 1339-1345 doi: 10.1038/labinvest.2010.105 pmid:20531292
64
Ito N, Kawata S, Tamura S, Shirai Y, Kiso S, Tsushima H, Matsuzawa Y. Positive correlation of plasma transforming growth factor-beta 1 levels with tumor vascularity in hepatocellular carcinoma. Cancer Lett 1995; 89(1): 45-48 doi: 10.1016/0304-3835(95)90156-6 pmid:7882301
65
Mazzocca A, Fransvea E, Lavezzari G, Antonaci S, Giannelli G. Inhibition of transforming growth factor beta receptor I kinase blocks hepatocellular carcinoma growth through neo-angiogenesis regulation. Hepatology 2009; 50(4): 1140-1151 doi: 10.1002/hep.23118 pmid:19711426
66
Wu K, Ding J, Chen C, Sun W, Ning BF, Wen W, Huang L, Han T, Yang W, Wang C, Li Z, Wu MC, Feng GS, Xie WF, Wang HY. Hepatic transforming growth factor beta gives rise to tumor-initiating cells and promotes liver cancer development. Hepatology 2012; 56(6): 2255-2267 doi: 10.1002/hep.26007 pmid:22898879
67
Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6(11): 1133-1141 doi: 10.1038/ni1261 pmid:16200068
68
Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 2007; 25: 821-852 pmid:17201677
69
Kolls JK, Lindén A. Interleukin-17 family members and inflammation. Immunity 2004; 21(4): 467-476 doi: 10.1016/j.immuni.2004.08.018 pmid:15485625
70
Dong C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 2008; 8(5): 337-348 doi: 10.1038/nri2295 pmid:18408735
71
Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupé P, Barillot E, Soumelis V. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol 2008; 9(6): 650-657 doi: 10.1038/ni.1613 pmid:18454150
72
Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 2008; 9(6): 641-649 doi: 10.1038/ni.1610 pmid:18454151
73
Notley CA, Inglis JJ, Alzabin S, McCann FE, McNamee KE, Williams RO. Blockade of tumor necrosis factor in collagen-induced arthritis reveals a novel immunoregulatory pathway for Th1 and Th17 cells. J Exp Med 2008; 205(11): 2491-2497 doi: 10.1084/jem.20072707 pmid:18936235
74
Zhang JP, Yan J, Xu J, Pang XH, Chen MS, Li L, Wu C, Li SP, Zheng L. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol 2009; 50(5): 980-989 doi: 10.1016/j.jhep.2008.12.033 pmid:19329213
75
Laan M, Cui ZH, Hoshino H, L?tvall J, Sj?strand M, Gruenert DC, Skoogh BE, Lindén A. Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. J Immunol 1999; 162(4): 2347-2352 pmid:9973514
76
Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 2008; 8(8): 618-631 doi: 10.1038/nrc2444 pmid:18633355
77
Kuang DM, Peng C, Zhao Q, Wu Y, Chen MS, Zheng L. Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology 2010; 51(1): 154-164 doi: 10.1002/hep.23291 pmid:19902483
78
Zhao Q, Xiao X, Wu Y, Wei Y, Zhu LY, Zhou J, Kuang DM. Interleukin-17-educated monocytes suppress cytotoxic T-cell function through B7-H1 in hepatocellular carcinoma patients. Eur J Immunol 2011; 41(8): 2314-2322 doi: 10.1002/eji.201041282 pmid:21674477
79
Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000; 13(5): 715-725 doi: 10.1016/S1074-7613(00)00070-4 pmid:11114383
80
Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003; 198(12): 1951-1957 doi: 10.1084/jem.20030896 pmid:14662908
Lo CH, Chang CM, Tang SW, Pan WY, Fang CC, Chen Y, Wu PY, Chen KY, Ma HI, Xiao X, Tao MH. Differential antitumor effect of interleukin-12 family cytokines on orthotopic hepatocellular carcinoma. J Gene Med 2010; 12(5): 423-434 doi: 10.1002/jgm.1452 pmid:20440753
83
Hu P, Hu HD, Chen M, Peng ML, Tang L, Tang KF, Matsui M, Belladonna ML, Yoshimoto T, Zhang DZ, Xiang R, Ren H. Expression of interleukins-23 and 27 leads to successful gene therapy of hepatocellular carcinoma. Mol Immunol 2009; 46(8-9): 1654-1662 doi: 10.1016/j.molimm.2009.02.025 pmid:19299021
84
Li J, Lau G, Chen L, Yuan YF, Huang J, Luk JM, Xie D, Guan XY. Interleukin 23 promotes hepatocellular carcinoma metastasis via NF-kappa B induced matrix metalloproteinase 9 expression. PLoS ONE 2012; 7(9): e46264 doi: 10.1371/journal.pone.0046264 pmid:23050001
85
Jiang R, Tan Z, Deng L, Chen Y, Xia Y, Gao Y, Wang X, Sun B. Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology 2011; 54(3): 900-909 doi: 10.1002/hep.24486 pmid:21674558
86
Lejeune D, Dumoutier L, Constantinescu S, Kruijer W, Schuringa JJ, Renauld JC. Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10. J Biol Chem 2002; 277(37): 33676-33682 doi: 10.1074/jbc.M204204200 pmid:12087100
87
Zhang W, Chen Y, Wei H, Zheng C, Sun R, Zhang J, Tian Z. Antiapoptotic activity of autocrine interleukin-22 and therapeutic effects of interleukin-22-small interfering RNA on human lung cancer xenografts. Clin Cancer Res 2008; 14(20): 6432-6439 doi: 10.1158/1078-0432.CCR-07-4401 pmid:18927282
88
Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Karow M, Flavell RA. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 2007; 27(4): 647-659 doi: 10.1016/j.immuni.2007.07.023 pmid:17919941
89
Park O, Wang H, Weng H, Feigenbaum L, Li H, Yin S, Ki SH, Yoo SH, Dooley S, Wang FS, Young HA, Gao B. In vivo consequences of liver-specific interleukin-22 expression in mice: Implications for human liver disease progression. Hepatology 2011; 54(1): 252-261 doi: 10.1002/hep.24339 pmid:21465510
90
Bertino G, Ardiri A, Malaguarnera M, Malaguarnera G, Bertino N, Calvagno GS. Hepatocellualar carcinoma serum markers. Semin Oncol 2012; 39(4): 410-433 doi: 10.1053/j.seminoncol.2012.05.001 pmid:22846859
91
Hu J, Xu Y, Hao J, Wang S, Li C, Meng S. MiR-122 in hepatic function and liver diseases. Protein Cell 2012; 3(5): 364-371 doi: 10.1007/s13238-012-2036-3 pmid:22610888
He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 2004; 5(7): 522-531 doi: 10.1038/nrg1379 pmid:15211354
94
Sugatani T, Hruska KA. Down-regulation of miR-21 biogenesis by estrogen action contributes to osteoclastic apoptosis. J Cell Biochem 2012; n/a doi: 10.1002/jcb.24471 pmid:23238785
95
Mott JL. MicroRNAs involved in tumor suppressor and oncogene pathways: implications for hepatobiliary neoplasia. Hepatology 2009; 50(2): 630-637 doi: 10.1002/hep.23010 pmid:19585622
96
Ladeiro Y, Couchy G, Balabaud C, Bioulac-Sage P, Pelletier L, Rebouissou S, Zucman-Rossi J. MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology 2008; 47(6): 1955-1963 doi: 10.1002/hep.22256 pmid:18433021
97
Braconi C, Patel T. MicroRNA expression profiling: a molecular tool for defining the phenotype of hepatocellular tumors. Hepatology 2008; 47(6): 1807-1809 doi: 10.1002/hep.22326 pmid:18506877
98
Jiang J, Gusev Y, Aderca I, Mettler TA, Nagorney DM, Brackett DJ, Roberts LR, Schmittgen TD. Association of microRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res 2008; 14(2): 419-427 doi: 10.1158/1078-0432.CCR-07-0523 pmid:18223217
99
Kutay H, Bai S, Datta J, Motiwala T, Pogribny I, Frankel W, Jacob ST, Ghoshal K. Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem 2006; 99(3): 671-678 doi: 10.1002/jcb.20982 pmid:16924677
100
Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T, Shimotohno K. Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene 2006; 25(17): 2537-2545 doi: 10.1038/sj.onc.1209283 pmid:16331254
101
Li W, Xie L, He X, Li J, Tu K, Wei L, Wu J, Guo Y, Ma X, Zhang P, Pan Z, Hu X, Zhao Y, Xie H, Jiang G, Chen T, Wang J, Zheng S, Cheng J, Wan D, Yang S, Li Y, Gu J. Diagnostic and prognostic implications of microRNAs in human hepatocellular carcinoma. Int J Cancer 2008; 123(7): 1616-1622 doi: 10.1002/ijc.23693 pmid:18649363
102
Wang Y, Lee AT, Ma JZ, Wang J, Ren J, Yang Y, Tantoso E, Li KB, Ooi LL, Tan P, Lee CG. Profiling microRNA expression in hepatocellular carcinoma reveals microRNA-224 up-regulation and apoptosis inhibitor-5 as a microRNA-224-specific target. J Biol Chem 2008; 283(19): 13205-13215 doi: 10.1074/jbc.M707629200 pmid:18319255
103
Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A, Zanetti KA, Ye QH, Qin LX, Croce CM, Tang ZY, Wang XW. Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology 2008; 47(3): 897-907 doi: 10.1002/hep.22160 pmid:18176954
104
Gramantieri L, Ferracin M, Fornari F, Veronese A, Sabbioni S, Liu CG, Calin GA, Giovannini C, Ferrazzi E, Grazi GL, Croce CM, Bolondi L, Negrini M. Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res 2007; 67(13): 6092-6099 doi: 10.1158/0008-5472.CAN-06-4607 pmid:17616664
105
Varnholt H, Drebber U, Schulze F, Wedemeyer I, Schirmacher P, Dienes HP, Odenthal M. MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma. Hepatology 2008; 47(4): 1223-1232 doi: 10.1002/hep.22158 pmid:18307259
106
Wong QW, Lung RW, Law PT, Lai PB, Chan KY, To KF, Wong N. MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1. Gastroenterology 2008; 135(1): 257-269 doi: 10.1053/j.gastro.2008.04.003 pmid:18555017
107
Pineau P, Volinia S, McJunkin K, Marchio A, Battiston C, Terris B, Mazzaferro V, Lowe SW, Croce CM, Dejean A. miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci USA 2010; 107(1): 264-269 doi: 10.1073/pnas.0907904107 pmid:20018759
108
Fan CG, Wang CM, Tian C, Wang Y, Li L, Sun WS, Li RF, Liu YG. miR-122 inhibits viral replication and cell proliferation in hepatitis B virus-related hepatocellular carcinoma and targets NDRG3. Oncol Rep 2011; 26(5): 1281-1286 pmid:21725618
109
Pedersen IM, Cheng G, Wieland S, Volinia S, Croce CM, Chisari FV, David M. Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 2007; 449(7164): 919-922 doi: 10.1038/nature06205 pmid:17943132
110
Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA. Science 2005; 309(5740): 1577-1581 doi: 10.1126/science.1113329 pmid:16141076
111
Zhang X, Zhang E, Ma Z, Pei R, Jiang M, Schlaak JF, Roggendorf M, Lu M. Modulation of hepatitis B virus replication and hepatocyte differentiation by microRNA-1. Hepatology 2011; 53(5): 1476-1485 doi: 10.1002/hep.24195 pmid:21520166
112
Sarasin-Filipowicz M, Krol J, Markiewicz I, Heim MH, Filipowicz W. Decreased levels of microRNA miR-122 in individuals with hepatitis C responding poorly to interferon therapy. Nat Med 2009; 15(1): 31-33 doi: 10.1038/nm.1902 pmid:19122656
113
van der Poorten D, George J. Disease-specific mechanisms of fibrosis: hepatitis C virus and nonalcoholic steatohepatitis. Clin Liver Dis 2008; 12(4): 805-824, ix (ix.) doi: 10.1016/j.cld.2008.07.003 pmid:18984468
114
Whittaker R, Loy PA, Sisman E, Suyama E, Aza-Blanc P, Ingermanson RS, Price JH, McDonough PM. Identification of microRNAs that control lipid droplet formation and growth in hepatocytes via high-content screening. J Biomol Screen 2010; 15(7): 798-805 doi: 10.1177/1087057110374991 pmid:20639500
115
Zheng L, Lv GC, Sheng J, Yang YD. Effect of miRNA-10b in regulating cellular steatosis level by targeting PPAR-alpha expression, a novel mechanism for the pathogenesis of NAFLD. J Gastroenterol Hepatol 2010; 25(1): 156-163 doi: 10.1111/j.1440-1746.2009.05949.x pmid:19780876
116
Cheung O, Puri P, Eicken C, Contos MJ, Mirshahi F, Maher JW, Kellum JM, Min H, Luketic VA, Sanyal AJ. Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression. Hepatology 2008; 48(6): 1810-1820 doi: 10.1002/hep.22569 pmid:19030170
117
Song G, Sharma AD, Roll GR, Ng R, Lee AY, Blelloch RH, Frandsen NM, Willenbring H. MicroRNAs control hepatocyte proliferation during liver regeneration. Hepatology 2010; 51(5): 1735-1743 doi: 10.1002/hep.23547 pmid:20432256
118
Castro RE, Ferreira DM, Zhang X, Borralho PM, Sarver AL, Zeng Y, Steer CJ, Kren BT, Rodrigues CM. Identification of microRNAs during rat liver regeneration after partial hepatectomy and modulation by ursodeoxycholic acid. Am J Physiol Gastrointest Liver Physiol 2010; 299(4): G887-G897 doi: 10.1152/ajpgi.00216.2010 pmid:20689055
119
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(2): 647-658 doi: 10.1053/j.gastro.2007.05.022 pmid:17681183
120
Marquez RT, Wendlandt E, Galle CS, Keck K, McCaffrey AP. MicroRNA-21 is upregulated during the proliferative phase of liver regeneration, targets Pellino-1, and inhibits NF-kappaB signaling. Am J Physiol Gastrointest Liver Physiol 2010; 298(4): G535-G541 doi: 10.1152/ajpgi.00338.2009 pmid:20167875
121
Lowes KN, Brennan BA, Yeoh GC, Olynyk JK. Oval cell numbers in human chronic liver diseases are directly related to disease severity. Am J Pathol 1999; 154(2): 537-541 doi: 10.1016/S0002-9440(10)65299-6 pmid:10027411
122
Libbrecht L, Desmet V, Van Damme B, Roskams T. Deep intralobular extension of human hepatic ‘progenitor cells’ correlates with parenchymal inflammation in chronic viral hepatitis: can ‘progenitor cells’ migrate? J Pathol 2000; 192(3): 373-378 doi: 10.1002/1096-9896(2000)9999:9999<::AID-PATH700>3.0.CO;2-5 pmid:11054721
123
Viebahn CS, Yeoh GC. What fires prometheus? The link between inflammation and regeneration following chronic liver injury. Int J Biochem Cell Biol 2008; 40(5): 855-873 doi: 10.1016/j.biocel.2007.11.025 pmid:18207446
Theise ND, Yao JL, Harada K, Hytiroglou P, Portmann B, Thung SN, Tsui W, Ohta H, Nakanuma Y. Hepatic ‘stem cell’ malignancies in adults: four cases. Histopathology 2003; 43(3): 263-271 doi: 10.1046/j.1365-2559.2003.01707.x pmid:12940779
126
Dumble ML, Croager EJ, Yeoh GC, Quail EA. Generation and characterization of p53 null transformed hepatic progenitor cells: oval cells give rise to hepatocellular carcinoma. Carcinogenesis 2002; 23(3): 435-445 doi: 10.1093/carcin/23.3.435 pmid:11895858
127
Korkaya H, Wicha MS. Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs 2007; 21(5): 299-310 doi: 10.2165/00063030-200721050-00002 pmid:17896836
128
Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea—a paradigm shift. Cancer Res 2006; 66(4): 1883-1890 ; discussion 1895-1896 pmid:16488983
129
Vermeulen L, De Sousa E Melo F, van der Heijden M, Cameron K, de Jong JH, Borovski T, Tuynman JB, Todaro M, Merz C, Rodermond H, Sprick MR, Kemper K, Richel DJ, Stassi G, Medema JP. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 2010; 12(5): 468-476 doi: 10.1038/ncb2048 pmid:20418870
130
Polyak K, Haviv I, Campbell IG. Co-evolution of tumor cells and their microenvironment. Trends Genet 2009; 25(1): 30-38 doi: 10.1016/j.tig.2008.10.012 pmid:19054589
131
Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, Oh EY, Gaber MW, Finklestein D, Allen M, Frank A, Bayazitov IT, Zakharenko SS, Gajjar A, Davidoff A, Gilbertson RJ. A perivascular niche for brain tumor stem cells. Cancer Cell 2007; 11(1): 69-82 doi: 10.1016/j.ccr.2006.11.020 pmid:17222791
132
Stauffer JK, Scarzello AJ, Andersen JB, De Kluyver RL, Back TC, Weiss JM, Thorgeirsson SS, Wiltrout RH. Coactivation of AKT and β-catenin in mice rapidly induces formation of lipogenic liver tumors. Cancer Res 2011; 71(7): 2718-2727 doi: 10.1158/0008-5472.CAN-10-2705 pmid:21324921
133
Schrader J, Gordon-Walker TT, Aucott RL, van Deemter M, Quaas A, Walsh S, Benten D, Forbes SJ, Wells RG, Iredale JP. Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology 2011; 53(4): 1192-1205 doi: 10.1002/hep.24108 pmid:21442631
134
Brunt EM, Blomenkamp K, Ahmed M, Ali F, Marcus N, Teckman J. Hepatic progenitor cell proliferation and liver injury in α-1-antitrypsin deficiency. J Pediatr Gastroenterol Nutr 2010; 51(5): 626-630 doi: 10.1097/MPG.0b013e3181e7ff55 pmid:20890217
135
Kitisin K, Shetty K, Mishra L, Johnson LB. Hepatocellular stem cells. Cancer Biomark 2007; 3(4-5): 251-262 pmid:17917154
136
Yamashita T, Honda M, Nakamoto Y, Baba M, Nio K, Hara Y, Zeng SS, Hayashi T, Kondo M, Takatori H, Yamashita T, Mizukoshi E, Ikeda H, Zen Y, Takamura H, Wang XW, Kaneko S. Discrete nature of EpCAM(+) and CD90(+) cancer stem cells in human hepatocellular carcinoma. Hepatology 2012; 57(4):1484-97 pmid:23174907
137
Jakubowski A, Ambrose C, Parr M, Lincecum JM, Wang MZ, Zheng TS, Browning B, Michaelson JS, Baetscher M, Wang B, Bissell DM, Burkly LC. TWEAK induces liver progenitor cell proliferation. J Clin Invest 2005; 115(9): 2330-2340 doi: 10.1172/JCI23486 pmid:16110324
138
Fausto N. Tweaking liver progenitor cells. Nat Med 2005; 11(10): 1053-1054 doi: 10.1038/nm1005-1053 pmid:16211039
139
Akhurst B, Matthews V, Husk K, Smyth MJ, Abraham LJ, Yeoh GC. Differential lymphotoxin-beta and interferon gamma signaling during mouse liver regeneration induced by chronic and acute injury. Hepatology 2005; 41(2): 327-335 doi: 10.1002/hep.20520 pmid:15660390
140
Uchio K, Graham M, Dean NM, Rosenbaum J, Desmoulière A. Down-regulation of connective tissue growth factor and type I collagen mRNA expression by connective tissue growth factor antisense oligonucleotide during experimental liver fibrosis. Wound Repair Regen 2004; 12(1): 60-66 doi: 10.1111/j.1067-1927.2004.012112.x-1 pmid:14974966
141
Nakamura K, Nonaka H, Saito H, Tanaka M, Miyajima A. Hepatocyte proliferation and tissue remodeling is impaired after liver injury in oncostatin M receptor knockout mice. Hepatology 2004; 39(3): 635-644 doi: 10.1002/hep.20086 pmid:14999682
142
Brooling JT, Campbell JS, Mitchell C, Yeoh GC, Fausto N. Differential regulation of rodent hepatocyte and oval cell proliferation by interferon gamma. Hepatology 2005; 41(4): 906-915 doi: 10.1002/hep.20645 pmid:15799032
143
Gangaraju VK, Lin H. MicroRNAs: key regulators of stem cells. Nat Rev Mol Cell Biol 2009; 10(2): 116-125 doi: 10.1038/nrm2621 pmid:19165214
144
Osborne JD, Flatow J, Holko M, Lin SM, Kibbe WA, Zhu LJ, Danila MI, Feng G, and Chisholm RL. Annotating the human genome with Disease Ontology. BMC Genomics .2009;10Suppl 1(S6.
145
Ji J, Yamashita T, Budhu A, Forgues M, Jia HL, Li C, Deng C, Wauthier E, Reid LM, Ye QH, Qin LX, Yang W, Wang HY, Tang ZY, Croce CM, Wang XW. Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells. Hepatology 2009; 50(2): 472-480 doi: 10.1002/hep.22989 pmid:19585654