Fibrogenesis and carcinogenesis in nonalcoholic steatohepatitis (NASH): Involvement of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs)

Cancers

Volumn 6, Issue 3, 2014, Pages 1220-1255

  Okazaki, Isao ^a,b   Noro, Takuji ^b   Tsutsui, Nobuhiro ^b   Yamanouchi, Eigoro ^b   Kuroda, Hajime ^b   Nakano, Masayuki ^c   Yokomori, Hiroaki ^d   Inagaki, Yutaka ^e  

^a INTERNATIONAL UNIVERSITY OF HEALTH AND WELFARE   (Japan)

^b International University of Health and Welfare   (Japan)

^c Ofuna Chuo Hospital   (Japan)

^d KITASATO UNIVERSITY MEDICAL CENTER   (Japan)

^e TOKAI UNIVERSITY SCHOOL OF MEDICINE   (Japan)

Author keywords

Bone marrow derived stem cell; Cancer invasion; Cancer metastasis; Cancer stem cell; Hepatic progenitor cell (HPC); Hepatocellular carcinoma (HCC); Matrix metalloproteinase (MMP); Nonalcoholic fatty liver disease (NAFLD); Nonalcoholic steatohepatitis (NASH); Tissue inhibitor of metalloproteinase (TIMP)

Indexed keywords

ADIPOCYTOKINE; CYTOKINE; LEPTIN; MATRIX METALLOPROTEINASE; TISSUE INHIBITOR OF METALLOPROTEINASE; TOLL LIKE RECEPTOR;

CANCER STEM CELL; CHRONIC LIVER DISEASE; FIBROGENESIS; HISTOPATHOLOGY; HUMAN; LIVER CARCINOGENESIS; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER FIBROSIS; MOLECULAR MECHANICS; NONALCOHOLIC FATTY LIVER; NONHUMAN; OXIDATIVE STRESS; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; TUMOR INVASION;

EID: 84903519577     PISSN: None     EISSN: 20726694     Source Type: Journal    
DOI: 10.3390/cancers6031220     Document Type: Review

References (170)

1. Fierbinteanu-Braticevicp, C.; Negreanu, L.; Tarantino, G. Is fatty liver always benign and should not consequently be treated? J. Physiol. Pharmacol. 2013, 64, 3-9.
2. Puri, P.; Sanyal, A. J. Nonalcoholic fatty liver disease. In Zakim and Boye's Hepatology, 6th ed.; Boyer, T. D., Manns, M. P., Sanyal, A. J., Eds.; Saunders: Philadelphia, PA, USA, 2006; pp. 941-968.
3. Pinzani, M. Pathophysiology of non-alcoholic steatohepatitis and basis for treatment. Dig. Dis. Sci. 2011, 29, 243-248.
4. Starley, B. Q.; Calcagno, C. J.; Harrison, S. A. Nonalcoholic fatty liver disease and hepatocellular carcinoma: A weighty connection. Hepatology 2010, 51, 1820-1832.
5. Bhala, N.; Jouness, R. I. K.; Bugianenesi, E. Epidemiology and natural history of patients with NAFLD. Curr. Pharm. Des. 2013, 19, 5169-5176.
6. Matteoni, C. H.; Younossi, Z. M.; Gramlich, T.; Boparai, N.; Liu, Y. C.; McCullough, A. J. Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity. Gastroenterology 1999, 116, 1413-1419.
7. Ludwig, J.; Viggiano, T. R.; McGill, D. B.; Ott, B. J. Nonalcoholic steatohepatitis. Mayo Clinic experience with a hitherto unnamed disease. Mayo Clin. Proc. 1980, 55, 434-438.
8. Hashimoto, E.; Tokushige, K. Prevalence, gender, ethnic variations, and prognosis of NASH. J. Gastroenterol. 2009, 44, 89-95.
9. Van der Poorten, D.; Samer, C. F.; Ramezani-Moghadam, M.; Coulter, S.; Kacevska, M.; Schrijnders, D.; Wu, L. E.; McLeod, D.; Bugianesi, E.; Komuta, M.; et al. Hepatic fat loss in advanced nonalcoholic steatohepatitis: Are alterations in serum adiponectin the cause? Hepatology 2013, 57, 2180-2188.
10. Kleiner, D.; Brunt, E. M.; Natta, M. V.; Behling, C.; Contos, M. J.; Cummings, O. W.; Ferrell, L. D.; Liu, Y.-C.; Torbenson, M. S.; Unalp-Arida, A.; et al. For the nonalcoholic steatohepatitis clinical research network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005, 41, 1313-1321.
11. Ertle, J.; Dechene, A.; Sowa, J.-A.; Penndorf, V.; Herzer, K.; Schlaak, J. F.; Gerken, G.; Syn, W.-K.; Canbay, A. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int. J. Cancer 2011, 128, 2436-2443.
12. Parkin, D. M.; Bray, F.; Ferlay, J.; Pisani, P. Global cancer statistics, 2002. CA Cancer J. Clin. 2005, 55, 74-108.
13. Venook, A. P.; Papandreou, C.; Furuse, J.; de Guevara, L. L. The incidence and epidemiology of hepatocellular carcinoma: A global and regional perspective. Oncologist 2010, 15, 5-13.
14. Okazaki, I.; Maruyama, K. Collagenase activity in experimental hepatic fibrosis. Nature 1974, 252, 49-50.
15. Okazaki, I.; Brinckerhoff, C. E.; Sinclair, J. R.; Sinclair, P. R.; Bonkovsky, H. L.; Harris, E. D., Jr. Iron increases collagenase production by rabbit synovial fibroblasts. J. Lab. Clin. Med. 1981, 97, 396-402.
16. Maruyama, K.; Feinman, L.; Okazaki, I.; Lieber, C. S. Direct measurement of neutral collagenase activity in homogenates from baboon and human liver. Biochim. Biophys. Acta 1981, 658, 124-131.
17. Maruyama, K.; Feinman, L.; Fainsilber, Z.; Nakano, M.; Okazaki, I.; Lieber, C. S. Mammalian collagenase increases in early alcoholic liver disease and decreases with cirrhosis. Life Sci. 1982, 30, 1379-1384.
18. Maruyama, K.; Okazaki, I.; Kobayashi, T.; Suzuki, H.; Kashiwazaki, K.; Tsuchiya, M. Collagenase production by rabbit liver cells in monolayer culture. J. Lab. Clin. Med. 1983, 102, 543-550.
19. Arai, M.; Niioka, M.; Maruyama, K.; Wada, N.; Fujimoto, N.; Nomiyama, T.; Tanaka, S.; Okazaki, I. Changes in serum levels of metalloproteinases and their inhibitors by treatment of chronic hepatitis C with interferon. Dig. Dis. Sci. 1996, 41, 995-1000.
20. Watanabe, T.; Niioka, M.; Hozawa, S.; Kameyama, K.; Hayashi, T.; Arai, M.; Ishikawa, A.; Okazaki, I. Gene expression of interstitial collagenase in both progressive and recovery phase of rat liver fibrosis induced by carbon tetrachloride. J. Hepatol. 2000, 33, 224-235.
21. Watanabe, T.; Niioka, M.; Ishikawa, A.; Hozawa, S.; Arai, M.; Maruyama, K.; Okada, A.; Okazaki, I. Dynamic change of cells expressing MMP-2 mRNA andMT1-MMP mRNA in the recovery from liver fibrosis in the rat. J. Hepatol. 2001, 35, 465-473.
22. Inagaki, Y.; Nemoto, T.; Kushida, M.; Sheng, Y.; Higashi, K.; Ikeda, K.; Kawada, N.; Shirasaki, F.; Takehara, K.; Sugiyama, K.; et al. Interferon alpha down-regulates collagen gene transcription and suppresses experimental hepatic fibrosis. Hepatology 2003, 38, 890-899.
23. Inagaki, Y.; Kushida, M.; Higashi, K.; Itoh, J.; Kawada, N.; Namikawa, K.; Kiyama, H.; Bou-Gharious, G.; Higashiyama, R.; Watanabe, T.; et al. Cell type-specific intervention of transforming growth factor beta/Smad signaling suppresses collagen gene expression and hepatic fibrosis in mice. Gastroenterology 2005, 129, 259-268.
24. Higashiyama, R.; Inagaki, Y.; Hong, Y. Y.; Kushida, M.; Nakao, S.; Niioka, M.; Watanabe, T.; Matsuzaki, Y.; Okano, H.; Shiota, G.; et al. Bone marrow-derived cells express matrix metalloproteinases and contribute to regression of liver fibrosis in mice. Hepatology 2007, 45, 213-222.
25. Inagaki, Y.; Kushida, M.; Shiota, G.; Kuwabara, I.; Itoh, J.; Moro, T.; Hong, Y. Y.; Nakao, S.; Higashiyama, R.; Okazaki, I.; et al. Hepatocyte growth factor suppresses profibrogenic signal transduction via nuclear export of Smad3 with galectin-7. Gastroenterology 2008, 134, 1180-1190.
26. Moro, T.; Shimoyama, Y.; Kushida, M.; Hong, Y. Y.; Nakao, S.; Higashiyama, R.; Sugioka, Y.; Inoue, H.; Okazaki, I.; Inagaki, Y. Glycyrrhizin and its metabolite inhibit Smad3-mediated type 1 collagen gene transcription and suppress experimental murine liver fibrosis. Life Sci. 2008, 83, 531-539.
27. Higashiyama, R.; Moro, T.; Nakao, S.; Mikami, K.; Fukumitsu, H.; Ikeda, K.; Adachi, E.; Bou-Gharios, G.; Okazaki, I.; Inagaki, Y. Negligible contribution of bone marrow-derived cells to collagen production during hepatic fibrogenesis in mice. Gastroenterology 2009, 137, 1459-1466.
28. Endo, H.; Niioka, M.; Sugioka, Y.; Itoh, J.; Kameyama, K.; Okazaki, I.; Ala-Aho, R.; Kahari, V. M.; Watanabe, T. Matrix metalloproteinase-13 promotes recovery from experimental liver cirrhosis in rats. Pathobiology 2011, 78, 239-252.
29. Watanabe, T.; Niioka, M.; Hozawa, S.; Sugioka, Y.; Arai, M.; Maruyama, K.; Okano, H.; Okazaki, I. Extracellular Matrix and the Liver-Approach to Gene Therapy; Okazaki, I., Ninomiya, Y., Friedman, S. L., Tanikawa, K., Eds.; Academic Press: New York, NY, USA, 2003; pp. 362-388.
30. Inagaki, Y.; Nemoto, T.; Nakao, A. Extracellular Matrix and the Liver-Approach to Gene Therapy; Okazaki, I., Ninomiya, Y., Friedman, S. L., Tanikawa, K., Eds.; Academic Press: New York, NY, USA, 2003; pp. 233-248.
31. Inagaki, Y.; Okazaki, I. Emerging insights into transforming growth factor-β and Smad signaling in hepatic fibrogenesis. Gut 2007, 56, 284-292.
32. Okazaki, I.; Wada, N.; Nakano, M.; Sato, A.; Takasaki, K.; Doi, M.; Kameyama, K.; Otani, Y.; Kubochi, K.; Niioka, M.; et al. Difference in gene expression for matrix metalloproteinase-1 between early and advanced hepatocellular carcinoma. Hepatology 1997, 25, 580-584.
33. Sugioka, Y.; Watanabe, T.; Inagaki, Y.; Kushida, M.; Niioka, M.; Endo, H.; Higashiyama, R.; Okazaki, I. C-Jun NH2-terminal kinase pathway is involved in constitutive matrix metalloproteinase-1 expression in a hepatocellular carcinoma-derived cell line. Int. J. Cancer 2004, 109, 867-874.
34. Endo, H.; Watanabe, T.; Sugioka, Y.; Niioka, M.; Inagaki, Y.; Okazaki, I. Activation of two distinct MAPK pathways governs constitutive expression of matrix metalloproteinase-1 in human pancreatic cancer cell lines. Int. J. Oncol. 2009, 35, 1237-1245.
35. Okazaki, I.; Inagaki, Y. Novel strategies for hepatocellular carcinoma based on MMPs science. Anticancer Agents Med. Chem. 2012, 12, 753-763.
36. Ong, J. P.; Elariny, H.; Collantes, R.; Younoszai, A.; Chandhoke, V.; Reines, H. D.; Goodman, Z.; Younossi, Z. M. Predictors of nonalcoholic steatohepatitis and advanced fibrosis in morbidly obese patients. Obes. Surg. 2005, 15, 310-315.
37. Day, C. P.; James, O. F. Steatohepatitis: A tale of two "hits"? Gastroenterology 1998, 114, 842-845.
38. Van der Poorten, D.; Milner, K. L.; Hui, J.; Hodge, A.; Trenell, M. I.; Kench, J. G.; London, R.; Peduto, T.; Chisholm, D. J.; George, J. Visceral fat: A key mediator of steatohepatitis in metabolic liver disease. Hepatology 2008, 48, 449-457.
39. Adams, L. A.; Sanderson, S.; Lindor, K. D.; Angulo, P. The histological course of nonalcoholic fatty disease: A longitudinal study of 103 patients with sequential liver biopsies. J. Hepatol. 2005, 42, 132-138.
40. Rector, R. S.; Morris, E. M.; Ridenhour, S.; Meers, G. M.; Hsu, F.-F.; Turk, J.; Ibdah, J. Selective hepatic insulin resistance in a murine model heterozygous for a mitochondrial trifunctional protein defect. Hepatology 2013, 57, 2213-2223.
41. Cohen, J. C.; Horton, J. D.; Hobbs, H. H. Human fatty liver disease: Old questions and new insights. Science 2011, 332, 1519-1523.
42. Ueno, T.; Sata, M.; Tanikawa, K. Cells responsible for extracellular matrix production in the liver. In Extracellular Matrix and the Liver Approach to Gene Therapy; Okazaki, I., Ninomiya, Y., Friedman, S. L., Tanikawa, K., Eds.; Academic Press: New York, NY, USA, 2003; pp. 89-103.
43. Friedman, S. L. Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. N. Eng. J. Med. 1993, 328, 1828-1835.
44. Li, D.; Friedman, S. L. Molecular mechanism of stellate cell activation and extracellular matrix remodeling. In Extracellular Matrix and the Liver Approach to Gene Therapy; Okazaki, I., Ninomiya, Y., Friedman, S. L., Tanikawa, K., Eds.; Academic Press: New York, NY, USA, 2003; pp. 155-178.
45. Pinzani, M.; Marra, F. Profibrogenic actions of hepatic stellate cells: Major intracellular signaling pathways. In Extracellular Matrix and the Liver Approach to Gene Therapy; Okazaki, I., Ninomiya, Y., Friedman, S. L., Tanikawa, K., Eds.; Academic Press: New York, NY, USA, 2003; pp. 207-231.
46. Siegmund, S. V.; Dooley, S.; Brenner, D. A. Molecular mechanisms of alcohol-induced hepatic fibrosis. Dig. Dis. 2005, 23, 264-274.
47. Miyahara, T.; Hazra, S.; Xiong, S.; Motomura, K.; She, H.; Tsukamoto, H. Peroxisome proliferator-activated receptor γ and hepatic stellate cell activation. In Extracellular Matrix and the Liver Approach to Gene Therapy; Okazaki, I., Ninomiya, Y., Friedman, S. L., Tanikawa, K., Eds.; Academic Press: New York, NY, USA, 2003; pp. 179-188.
48. Zhu, N.-L.; Asahina, K.; Wang, J.; Ueno, A.; Lazaro, R.; Miyaoka, Y.; Miyajima, A.; Tsukamoto, H. Hepatic stellate cell-derived Delta-like Homolog 1 (DLK1) protein in liver regeneration. J. Biol. Chem. 2012, 287, 10355-10367.
49. Kisseleva, T.; Cong, M.; Paik, Y.; Scholten, D.; Jiang, C.; Benner, C.; Iwaisako, K.; Moore-Morris, T.; Scott, B.; Tsukamoto, H.; et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc. Natl. Acad. Sci. USA 2012, 109, 9448-9453.
50. Uyama, N.; Iimuro, Y.; Kawada, N.; Reynaert, H.; Suzumura, K.; Hirano, T.; Kuroda, N.; Fujimoto, J. Fascin, a novelmarker of human hepatic stellate cells, may regulate their proliferation, migration, and collagen gene expression through the FAK-PI3K-Akt pathway. Lab. Invest. 2012, 92, 7-71.
51. Motoyama, H.; Komiya, T.; Thuy le, T. T.; Enomoto, M.; Morikawa, H.; Iwai, S.; Uchida-Kobayashi, S.; Fujii, H.; Hagihara, A.; Kawamura, E.; et al. Cytoglobin is expressed in hepatic stellate cells, but not in myofibroblasts, in normal and fibrotic human liver. Lab. Invest. 2014, 94, 192-207.
52. Neubauer, K.; Krueger, M.; Quondamatteo, F.; Knittel, T.; Saile, B.; Ramadori, G. Transforming growth factor-β1 stimulates the synthesis of basement membrane proteins laminin, collagen type IV and entactin in rat liver sinusoidal endothelial cells. J. Hepatol. 1999, 31, 692-702.
53. Ramadori, G.; Neubauer, K. Role of sinusoidal endothelial cells in liver inflammation and repair. In Extracellular Matrix and the Liver Approach to Gene Therapy; Okazaki, I., Ninomiya, Y., Friedman, S. L., Tanikawa, K., Eds.; Academic Press: New York, NY, USA, 2003; pp. 135-151.
54. Forbes, S. J.; Russo, F. P.; Rey, V.; Burra, P.; Rugge, M.; Wright, N. A.; Alison, M. R. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 2004, 126, 955-963.
55. Russo, F. P.; Alison, M. R.; Bigger, B. W.; Amofah, E.; Florou, A.; Amin, F.; Bou-Gharios, G.; Jeffery, R.; Iredale, J. P.; Forbes, S. J. The bone marrow functionally contributes to liver fibrosis. Gastroenterology 2006, 130, 1807-1821.
56. Baba, S.; Fujii, H.; Hirose, T.; Yasuchika, K.; Azuma, H.; Hoppo, T.; Naito, M.; Machimoto, T.; Ikai, I. Commitment of bone marrow cells to hepatic stellate cells in mouse. J. Hepatol. 2004, 40, 255-260.
57. Kisseleva, T.; Uchiyama, H.; Feirt, N.; Quintana-Bustamante, O.; Segovia, J. C.; Schwabe, R. F.; Brenner, D. A. Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. J. Hepatol. 2006, 45, 429-438.
58. Miyata, E.; Masuya, M.; Yoshida, S.; Nakamura, S.; Kato, K.; Sugimoto, Y.; Shibasaki, T.; Yamamura, K.; Ohishi, K.; Nishii, K.; et al. Hematopoietic origin of hepatic stellate cells in the adult liver. Blood 2008, 111, 2427-2435.
59. Inagaki, Y.; Higashiyama, R. Interplay between bone marrow and liver in the pathogenesis of hepatic fibrosis. Hepatol. Res. 2012, 10, 1-6.
60. Jiao, J.; Sastre, D.; Fiel, M. I.; Lee, U. E.; Ghiassi-Nejad, Z.; Ginhoux, E.; Vivier, E.; Friedman, S. L.; Merad, M.; Aloman, C. Dendritic cell regulation of carbon tetrachloride-induced murine liver fibrosis regression. Hepatology 2012, 55, 244-255.
61. Pradere, J.-P.; Kluwe, J.; de Minicis, S.; Jiao, J.-J.; Gwak, G.-Y.; Dapito, D. H.; Jang, M.-K.; Guenther, N. D.; Mederacke, I.; Friedman, R.; et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 2013, 58, 1461-1473.
62. Xie, G.; Karaca, G.; Swiderska-Syn, M.; Michelotti, G. A.; Kruger, L.; Chen, Y.; Premont, R. T.; Choi, S. S.; Diehl, A. M. Cross-talk between notch and hedgehog regulates hepatic stellate cell fate in mice. Hepatology 2013, 58, 1801-1813.
63. Nieto, N.; Greenwel, P.; Friedman, S. L.; Zhang, F.; Dannenberg, A. J.; Cederbaum, A. I. Ethanol and arachidonic acid increase alpha 2(1) collagen expression in rat hepatic stellate cells overexpressing cytochrome P450 2E1. Role of H2O2 and cyclooxygenase-2. J. Biol. Chem. 2000, 275, 20136-20145.
64. Greenwel, P.; Dominguez-Rosales, J. A.; Mavi, G.; Rivas-Estilla, A. M.; Rojkind, M. Hydrogen peroxide: A link between acetaldehyde-elicited alpha (I) collagen gene up-regulation and oxidative stress in mouse hepatic stellate cells. Hepatology 2000, 31, 109-116.
65. Alkhouri, N.; Dixon, L. J.; Feldstein, A. E. Lipotoxicity in nonalcoholic fatty liver disease: Not all lipids are created equal. Expert Rev. Gastroenterol. Hepatol. 2009, 3, 445-451.
66. Johnson, N. A.; George, J. Fitness versus fatness: Moving beyond weight loss in nonalcoholic fatty liver disease. Hepatology 2010, 52, 370-381.
67. Paradis, V.; Perlemuter, G.; Bonvoust, F.; Dargere, D.; Parfait, B.; Vidaud, M.; Conti, M.; Huet, S.; Ba, N.; Buffet, C.; et al. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: A potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 2001, 34, 738-744.
68. Ikeda, R.; Ishii, K.; Hoshikawa, Y.; Azumi, I.; Arakaki, Y.; Yasui, T.; Matsuura, S.; Matsumi, Y.; Kono, Y.; Mizuta, Y.; et al. Reactive oxygen species and NADPH oxidase 4 induced by transforming growth factor beta 1 are therapeutic targets of polyenylphosphatidylcholine in the suppression of human hepatic stellate cell activation. Inflamm. Res. 2011, 60, 597-604.
69. Li, J.; Fan, R.; Zhao, S.; Liu, L.; Guo, S.; Wu, N.; Zhang, W.; Chen, P. Reactive oxygen species released from hypoxic hepatocytes regulates MMP-2 expression in hepatic stellate cells. Int. J. Mol. Sci. 2011, 12, 2434-2447.
70. Asano, T.; Watanabe, K.; Kubota, N.; Gunji, T.; Omata, M.; Kadowaki, T.; Ohnishi, S. Adiponectin knockout mice on high fat diet develop fibrosing steatohepatitis. J. Gastroenterol. Hepatol. 2009, 24, 1669-1676.
71. Choi, S. S.; Syn, W. K.; Karaka, G. F.; Omenetti, A.; Moylan, C. A.; Witek, R. P.; Agboola, K. M.; Jung, Y.; Michelotti, G. A.; Diehl, A. M. Leptin promotes the myofibroblastic phenotype in hepatic stellate cells by activating the hedgehog pathway. J. Biol. Chem. 2010, 285, 36551-36560.
72. Marra, F.; Navari, N.; Vivoli, E.; Galastri, S.; Provenzano, A. Modulation of liver fibrosis by adipokines. Dig. Dis. 2011, 29, 371-376.
73. Bian, Z.; Ma, X. Liver fibrogenesis in non-alcoholic steatohepatitis. Front. Physiol. 2012, 3, 248.
74. Wree, A.; Broderick, L.; Canbay, A.; Hoffman, H. M.; Feldstein, A. E. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 627-636.
75. Sanyal, A. J.; Chalasani, N.; Kowdley, K. V.; McCullough, A.; Diehl, A. M.; Bass, N. M.; Neuschwander-Tetri, B. A.; Lavine, J. E.; Tonascia, J.; Unalp, A.; et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Eng. J. Med. 2010, 362, 1675-1685.
76. McCarty, M. F. Full-spectrum anti-oxidant therapy featuring astaxanthin coupled with lipoprivic strategies and salsalate for management of non-alcoholic fatty liver disease. Med. Hypotheses 2011, 77, 550-556.
77. Gastaldelli, A.; Harrison, S.; Belfort-Aguiar, R.; Hardies, I.; Balas, B.; Schenker, S.; Cusi, K. Pioglitazone in the treatment of NASH: The role of adiponectin. Aliment. Pharmacol. Ther. 2010, 32, 769-775.
78. Medici, V.; Ali, M. R.; Seo, S.; Aoki, C. A.; Rossaro, L.; Kim, K.; Fuller, W. D.; Vidovszky, T. J.; Smith, W.; Jiang, J. X.; et al. Increased soluble leptin receptor levels in morbidly obese patients with insulin resistance and nonalcoholic fatty liver disease. Obesity (Silver Spring) 2010, 18, 2268-2273.
79. Moro, T.; Nakao, S.; Sumiyoshi, H.; Ishii, T.; Miyazawa, M.; Ishii, N.; Inagaki, Y. Direct contribution of mitochondrial oxidative stress to hepatic fibrogenesis. Hepatology 2013, 58, 584A.
80. De Minicis, S.; Day, C.; Svegliati-Baroni, G. From NAFLD to NASH and HCC: Pathogenetic mechanisms and therapeutic insights. Curr. Pharm. Des. 2013, 19, 5239-5249.
81. Mari, M.; Caballero, F.; Colell, A.; Morales, A.; Caballeria, J.; Fernandez, A.; Enrich, C.; Fernandez-Checa, J. C.; Garcia-Ruiz, C. Mitochondrial free cholesterol loading sensitizes to TNF-and Fas-mediated steatohepatitis. Cell Met. 2006, 4, 185-198.
82. Teratani, T.; Tomita, K.; Suzuki, T.; Oshikawa, T.; Yokoyama, H.; Shimamura, K.; Tominaga, S.; Hiroi, S.; Irie, R.; Okada, Y.; et al. A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells. Gastroenterology 2012, 42, 152-164.
83. Aleffi, S.; Navari, N.; Delogu, W.; Galastri, S.; Novo, E.; Rombouts, K.; Pinzani, M.; Parola, M.; Marra, F. Mammalian target of rapamycin mediates the angiogenic effects of leptin in human hepatic stellate cells. Am. J. Physiol. Gastroenterol. Physiol. 2011, 301, G210-G219.
84. Seki, E.; Brenner, D. A. Toll-like receptors and adaptor molecules in liver disease: Update. Hepatology 2008, 48, 322-335.
85. Yang, S. Q.; Lin, H. Z.; Lane, M. D.; Clemens, M.; Diehl, A. M. Obesity increases sensitivity to endotoxin liver injury: Implications for the pathogenesis of steatohepatitis. Proc. Natl. Acad. Sci. USA 1997, 94, 2557-2562.
86. Seki, E.; de Meicis, S.; Osterricher, C. H.; Kluwe, J.; Osawa, Y.; Brenner, D. A.; Schwabe, R. F. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat. Med. 2007, 13, 1324-1332.
87. Jagavelu, K.; Routray, C.; Shergill, U.; O'Hara, S. P.; Faubion, W.; Shah, V. H. Endothelial cell toll-like receptor 4 regulates fibrosis-associated angiogenesis in the liver. Hepatology 2010, 52, 590-601.
88. Shirai, Y.; Yoshiji, H.; Noguchi, R.; Kaji, K.; Aihara, Y.; Douhara, A.; Moriya, K.; Namisaki, T.; Kawaratani, H.; Fukui, H. Cross talk between toll-like receptor-4 signaling and angiotensin-II in liver fibrosis development in the rat model of non-alcoholic steatohepatitis. J. Gastroenterol. Hepatol. 2013, 28, 723-730.
89. Henao-Mejia, J.; Elinav, E.; Jin, C.-C.; Hao, L.; Mehal, W. Z.; Strowig, T.; Thaiss, C. A.; Kau, A. L.; Eisenbarth, S. C.; Jurczak, M. J.; et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012, 482, 179-185.
90. Li, L.; Chen, L.; Hu, L.; Liu, Y.; Sun, H. Y.; Tang, Y.-J.; Chang, Y.-X.; Tu, Q.-Q.; Feng, G.-S.; Shen, F.; et al. Nuclear factor high-mobility group box1 mediating the activation of Toll-like receptor 4 signaling in hepatocytes in the early stage of nonalcoholic fatty liver disease in mice. Hepatology 2011, 54, 1620-1630.
91. Chen, A.; Tang, Y.; Davis, V.; Hsu, F.-F.; Kennedy, S. M.; Song, H.; Turk, J.; Brunt, E. M.; Newberry, E. P.; Davidson, N. O. Liver fatty acid binding protein (L-Fabp) modulates murine stellate cell activation and diet-induced nonalcoholic fatty liver disease. Hepatology 2013, 57, 2202-2212.
92. Ratziu, V.; Charlotte, F.; Bernhardt, C.; Giral, P.; Halbron, M.; Lenaour, G.; Hartmann-Heurtier, A.; Bruckert, E.; Poynard, T.; LIDO Study Group. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: Results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 2010, 51, 445-453.
93. Miura, K.; Yang, L.; van Rooijen, N.; Ohnishi, H.; Seki, E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 302, G1310-G1321.
94. Tosello-Trampont, A.-C.; Landes, S. G.; Nguyen, V.; Novobrantseva, T. I.; Hahn, Y. S. Kupffer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-α production. J. Biol. Chem. 2012, 287, 40161-40172.
95. Carpino, G.; Renzi, A.; Onori, P.; Gaudio, E. Role of hepatic progenitor cells in nonalcoholic fatty liver disease development: Cellular cross-talks and molecular networks. Int. J. Mol. Sci. 2013, 14, 20112-20130.
96. Van Hul, N. K. M.; Abarca-Quinones, J.; Sempoux, C.; Horsmans, Y.; Leclercq, I. A. Relation between liver progenitor cell expansion and extracellular matrix deposition in a CDE-induced murine model of chronic liver injury. Hepatology 2009, 49, 1625-1635.
97. Boulter, L.; Govaere, O.; Bird, T. G.; Radulescu, S.; Ramachandran, P.; Pellicoro, A.; Ridgway, R. A.; Seo, S. S.; Spee, B.; Rooijen, N. V.; et al. Macrophage derived Wnt signaling opposes Notch signaling in a Numb mediated manner to specify HPC fate in chronic liver disease in human and mouse. Nat. Med. 2012, 18, 572-579.
98. Nobili, V.; Carpino, G.; Alisi, A.; Franchitto, A.; Alpini, G.; de Vito, R.; Onori, P.; Alvaro, D.; Gaudio, E. Hepatic progenitor cells activation, fibrosis, and adipokines production in pediatric nonalcoholic fatty liver disease. Hepatology 2012, 56, 2142-2153.
99. Friedman, S. L. Convergent pathways that cause hepatic fibrosis in NASH. Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 71-72.
100. Wagner, M.; Zollner, G.; Trauner, M. Nuclear receptors in liver disease. Hepatology 2011, 53, 1023-1034.
101. Belfort, R.; Harrison, S. A.; Brown, K.; Darland, C.; Finch, J.; Hardies, J.; Balas, B.; Gastaldeli, A.; Tio, F.; Pulcini, J.; et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N. Eng. J. Med. 2006, 355, 2297-2307.
102. Syn, W.-K.; Choi, S. S.; Liaskou, E.; Karaca, G. F.; Agboola, K. M.; Oo, Y. H.; Mi, Z.; Pereira, T. A.; Zdanowicz, M.; Malladi, P.; et al. Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology 2011, 53, 106-115.
103. Okazaki, I.; Watanabe, T.; Hozawa, S.; Niioka, M.; Arai, M.; Maruyama, K. Minireview Series for the 50th Volume: Reversibility of hepatic fibrosis: From the first report of collagenase in the liver to the possibility of gene therapy for recovery. Keio J. Med. 2001, 50, 58-65.
104. Arthur, M. J.; Friedman, S. L.; Roll, F. J.; Bissell, D. M. Lipocytes from normal rat liver release a neutral metalloproteinase that degrades basement membrane (type IV collagen). J. Clin. Invest. 1989, 84, 1076-1085.
105. Takahara, T.; Furui, K.; Funaki, J.; Nakayama, Y.; Itoh, H.; Miyabayashi, C.; Sato, H.; Seiki, M.; Ooshima, A.; Watanabe, A. Increased expression of matrix metalloproteinase-II in experimental liver fibrosis in rats. Hepatology 1995, 21, 787-795.
106. Takahara, T.; Furui, K.; Yata, Y.; Jin, B.; Zhang, L. P.; Nambu, S.; Sato, H.; Seiki, M.; Watanabe, A. Dual expression of matrix metalloproteinase-2 and membrane-type-1-matrix metalloproteinase in fibrotic human livers. Hepatology 1997, 26, 1521-1529.
107. Okazaki, I.; Nabeshima, K. Introduction: MMPs, ADAMs/ADAMTSs research products to achieve big dream. Anticancer Agents Med. Chem. 2012, 12, 688-706.
108. Iredale, J. P.; Benyon, R. C.; Pickering, J.; McCullen, M.; Northrop, M.; Pawley, S.; Hovell, C.; Arthur, M. J. Mechanism of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J. Clin. Invest. 1998, 102, 538-549.
109. Yoshiji, H.; Kuriyama, S.; Yoshii, J.; Ikenaga, Y.; Noguchi, R.; Nakatani, T.; Tsujinoue, H.; Yanase, K.; Namisaki, T.; Imazu, H.; et al. Tissue inhibitor of metalloproteinase-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse. Hepatology 2002, 36, 850-860.
110. Ljumovic, D.; Diamantis, I.; Alegakis, A. K.; Kouroumalis, E. A. Differential expression of matrix metalloproteinases in viral and non-viral chronic liver diseases. Clin. Chim. Acta 2004, 349, 203-211.
111. D'Amico, F.; Consolo, M.; Amoroso, A.; Skarmoutsou, E.; Mauceri, B.; Stivala, F.; Malaponte, G.; Bertino, G.; Neri, S.; Mazzarino, M. C. Liver immunolocalization and plasma levels of MMP-9 in non-alcoholic steatohepatitis (NASH) and hepatitis C infection. Acta Histochem. 2010, 112, 474-481.
112. Cao, Q.; Mak, K.; Lieber, C. S. Leptin represses matrix metalloproteinase-1 gene expression in LX2 human hepatic stellate cells. J. Hepatol. 2007, 46, 124-133.
113. Wanninger, J.; Walter, R.; Bauer, S.; Eisinger, K.; Schaffler, A.; Dorn, C.; Weiss, T. S.; Hellerbrand, C.; Buechler, C. MMP-9 activity is increased by adiponectin in primary human hepatocytes but even negatively correlates with serum adiponectin in a rodent model of non-alcoholic steatohepatitis. Exp. Mol. Pathol. 2011, 91, 603-607.
114. Tarrats, N.; Moles, A.; Garcia-Ruiz, C.; Fernandez-Checa, J. C.; Mari, M. Critical role of tumor necrosis factor receptor 1, but not 2, in hepatic stellate cell proliferation, extracellular matrix remodeling, and liver fibrogenesis. Hepatology 2011, 54, 319-327.
115. Adams, L. A.; Lymp, J. F.; St. Sauver, J.; Sanderson, S. O.; Lindor, K. D.; Feldstein, A.; Angulo, P. The natural history of nonalcoholic fatty liver disease: A population-based cohort study. Gastroenterology 2005, 129, 113-121.
116. Ascha, M. S.; Hanouneh, I. A.; Lopez, R.; Tamimi, T. A.-R.; Feldstein, A. F.; Zein, N. N. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010, 51, 1972-1978.
117. Fu, J.; Chen, Y.; Cao, J.; Luo, T.; Qian, Y.; Yang, W.; Ren, Y.; Su, B.; Cao, G.; Yang, Y.; et al. P28 GANK overexpression accelerates hepatocellular carcinoma invasiveness and metastasis via phosphoinositol 3-kinae/AKT/hypoxia-inducible factor-1α pathways. Hepatology 2011, 53, 181-192.
118. Hayashi, Y.; Osanai, M.; Lee, G. H. Fascin-1 expression correlates with repression of E-cadherin expression in hepatocellular carcinoma cells and augments their invasiveness in combination with matrix metalloproteinases. Cancer Sci. 2011, 102, 1226-1235.
119. Wang, B.; Hsu, S.; Majumder, S.; Kutay, H.; Huang, W.; Jacob, S. T.; Ghoshal, K. TGFbeta-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3. Oncogene 2010, 29, 1787-1797.
120. Man, K.; Ng, K. T. P.; Xu, A.; Cheng, Q.; Lo, C. M.; Xiao, J. W.; Sun, B. S.; Lim, Z. X. H.; Cheung, J. S.; Wu, E. X.; et al. Suppression of tumor growth and metastasis by adiponectin in nude mice through inhibition of tumor angiogenesis and downregulation of Rho kinase/IFN-inducible protein 10/matrix metalloproteinase 9 signaling. Clin. Cancer Res. 2010, 16, 967-977.
121. Gentilini, A.; Rombouts, K.; Galastri, S.; Caligiuri, A.; Mingarelli, E.; Mello, T.; Marra, F.; Mantero, S.; Roncalli, M.; Invernizzi, P.; et al. Role of the stromal-derived factor-1 (SDF-1)-CXCR4 axis in the interaction between hepatic stellate cells and cholangiocarcinoma. J. Hepatol. 2012, 57, 813-820.
122. Marrero, J. A.; Fontana, R. J.; Su, G. L.; Conjeevaram, H. S.; Emick, D. M.; Lok, A. S. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 2002, 36, 1349-1354.
123. Ratziu, V.; Bonyhay, L.; di Charlotte, F.; Cavallaro, L.; Sayegh-Tainturier, M. H.; Giral, P.; Grimaldi, A.; Opolon, P.; Poynard, T. Survival, liver failure and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology 2002, 35, 1485-1493.
124. Paradis, V.; Zalinski, S.; Chelbi, E.; Guedj, N.; Degos, F.; Vilgrain, V.; Bedossa, P.; Belghiti, J. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: A pathological analysis. Hepatology 2009, 49, 851-859.
125. Zhang, D. Y.; Friedman, S. L. Fibrosis-dependent mechanism of hepatocarcinogenesis. Hepatology 2012, 56, 769-775.
126. Yin, C.; Evason, K. J.; Asahina, K.; Stainer, D. Y. R. Hepatic stellate cells in liver development, regeneration, and cancer. J. Clin. Invest. 2013, 123, 1902-1910.
127. Muir, K.; Hazim, A.; He, Y.; Peyressatre, M.; Kim, D.-Y.; Song, X.; Beretta, L. Proteomic and lipidomic signatures of lipid metabolism in NASH-associated hepatocellular carcinoma. Cancer Res. 2013, 73, 4722-4731.
128. Page, J. M.; Harrison, S. A. NASH and HCC. Clin. Liver Dis. 2009, 13, 631-647.
129. Bohinc, B. N.; Diehl, A. M. Mechanism of disease progression in NASH: New paradigms. Clin. Liver Dis. 2012, 16, 549-565.
130. Weiskopf, K.; Ring, A. M.; Ho, C. C. M.; Volkmer, J.-P.; Levin, A. M.; Volkmer, A. K.; Özkan, E.; Fernhoff, N. B.; van de Rijn, M.; Weissman, I. L.; et al. Engineered SIRPα variants as immunotherapeutic adjuvants to anti-cancer antibodies. Science 2013, 341, 88-91.
131. Yoshimoto, S.; Loo, T. M.; Atarashi, K.; Kanda, H.; Sato, S.; Oyadomari, S.; Iwakura, Y.; Oshima, K.; Morita, H.; Hattori, M.; et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013, 499, 97-101.
132. Lin, H.; Yan, J.; Wang, Z.; Hua, F.; Yu, J.; Sun, W.; Li, K.; Liu, H.; Yang, H.; Lv, Q.; et al. Loss of immunity-supported senescence enhances susceptibility to hepatocellular carcinogenesis and progression in Toll-like receptor 2-deficient mice. Hepatology 2013, 57, 171-182.
133. Wang, Z.; Yan, J.; Lin, H.; Hua, F.; Wang, X.; Liu, H.; Lv, X.; Yu, J.; Mi, S.; Wang, J.; et al. Toll-like receptor 4 activity protects against hepatocellular tumorigenesis and progression by regulating expression of DNA repair protein Ku70 in mice. Hepatology 2013, 57, 1869-1881.
134. Murphy, S. K.; Yang, H.; Moylan, C. A.; Pang, H.; Dellinger, A.; Abdelmalek, M. F.; Garrett, M.; Ashley-Koch, A.; Suzuki, A.; Tillmann, H. L.; et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology 2013, 145, 1076-1087.
135. Arii, S.; Mise, M.; Harada, T.; Furutani, M.; Ishigami, S.; Niwano, M.; Mizumoto, M.; Fukumoto, M.; Imamura, M. Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. Hepatology 1996, 24, 316-322.
136. Ashida, K.; Nakatsukasa, H.; Higashi, T.; Ohguchi, S.; Hino, N.; Nouso, K.; Urabe, Y.; Yoshida, K.; Kinugasa, N.; Tsuji, T. Cellular distribution of 92-kd type IV collagenase B in human hepatocellular carcinoma. Am. J. Pathol. 1996, 149, 1803-1811.
137. Ogata, R.; Torimura, T.; Kin, M.; Ueno, T.; Tateishi, Y.; Kuromatsu, R.; Shimauchi, Y.; Sakamoto, M.; Tamaki, S.; Sata, M.; et al. Increased expression of membrane type 1 matrix metalloproteinases and matrix metalloproteinase-2 with tumor differentiation in hepatocellular carcinomas. Hum. Pathol. 1999, 30, 443-450.
138. Sakamoto, Y.; Mafune, K.; Mori, M.; Shiraishi, T.; Imamura, H.; Mori, M.; Takayama, T.; Makuuchi, M. Overexpression of MMP-9 correlates with growth of small hepatocellular carcinoma. Int. J. Oncol. 2000, 17, 237-243.
139. Maatta, M.; Soini, Y.; Liakka, A.; Autio-Harmainen, H. Differential expression of matrix metalloproteinase (MMP)-2, MMP-9, and membrane type 1-MMP in hepatocellular and pancreatic adenocarcinoma: Implications for tumor progression and clinical prognosis. Clin. Cancer Res. 2000, 6, 2726-2734.
140. Syed, I.; Rathod, J.; Parmar, M.; Parmar, M.; Corcoran, G. B.; Ray, S. D. Matrix metalloproteinase-9,-10, and-12, MDM2 and p53 expression in mouse liver during diethylnitrosamine-induced oxidative stress and genomic injury. Mol. Cell Biochem. 2012, 365, 351-361.
141. Fang, J.-H.; Zhou, H.-C.; Zeng, C.; Yang, J.; Liu, Y.; Huang, X.; Zhang, J.-P.; Guan, X.-Y.; Zhuang, S.-M. MicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression. Hepatology 2011, 54, 1729-1740.
142. Sato, H.; Takino, T.; Okada, Y.; Cao, J.; Shinagawa, A.; Yamamoto, E.; Seiki, M. A matrix metalloproteinase expressed on the surface of invasive tumor cells. Nature 1994, 370, 61-65.
143. Strongin, A. Y.; Collier, I.; Bannikov, G.; Marmer, B. L.; Grant, G. A.; Goldberg, G. L. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloproteinase. J. Biol. Chem. 1995, 270, 5331-5338.
144. Yamamoto, H.; Itoh, F.; Adachi, Y.; Sakamoto, H.; Adachi, M.; Hinoda, Y.; Imai, K. Relation of enhanced secretion of active matrix metalloproteinases with tumor spread in human hepatocellular carcinoma. Gastroenterology 1997, 112, 1290-1296.
145. Musso, O.; Theret, N.; Campion, J. P.; Turlin, B.; Milani, S.; Grappone, C.; Clement, B. In situ detection of matrix metalloproteinase-2 (MMP2) and the metalloproteinase inhibitor TIMP2 transcripts in human primary hepatocellular carcinoma and in liver metastasis. J. Hepatol. 1997, 26, 593-605.
146. Harada, T.; Arii, S.; Imamura, T.; Higashitsuji, H.; Furutani, M.; Niwano, M.; Ishigami, S.; Fukumoto, M.; Seiki, M.; Sato, H.; et al. Membrane-type matrix metalloproteinase-1 (MT1-MMP) gene is overexpressed in highly invasive hepatocellular carcinoma. J. Hepatol. 1998, 28, 231-239.
147. Theret, N.; Musso, O.; L'Helgoualc'h, A.; Campion, J.-P.; Clement, B. Differential expression and origin of membrane-type 1 and 2 matrix metalloproteinases (MT-MMPs) in association with MMP2 activation in injured human livers. Am. J. Pathol. 1998, 153, 945-954.
148. Yamamoto, H.; Itoh, F.; Adachi, Y.; Fukushima, H.; Itoh, H.; Sasaki, S.; Hinoda, Y.; Imai, K. Messenger RNA expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human hepatocellular carcinoma. Jpn. J. Clin. Oncol. 1999, 29, 58-62.
149. McKenna, G. J.; Chen, Y.; Smith, R. M.; Meneghetti, A.; Ong, C.; McMaster, R.; Scudamore, C. H.; Chung, S. W. A role for matrix metalloproteinases and tumor host interaction in hepatocellular carcinomas. Am. J. Surg. 2002, 183, 588-594.
150. Giannelli, G.; Bergamini, C.; Marinosci, F.; Fransvea, E.; Quaranta, M.; Lupo, L.; Schiraldi, O.; Antonaci, S. Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma. Int. J. Cancer 2002, 97, 425-431.
151. Ishii, Y.; Nakasato, Y.; Kobayashi, S.; Yamazaki, Y.; Aoki, T. A study on angiogenesis-related marix metalloproteinase networks in primary hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 2003, 22, 461-470.
152. Gao, Z. H.; Tretiakova, M. S.; Liu, W. H.; Gong, C.; Farris, P. D.; Hart, J. Association of E-cadherin, matrix metalloproteinases, and tissue inhibitors of metalloproteinases with the progression and metastasis of hepatocellular carcinoma. Mod. Pathol. 2006, 19, 533-540.
153. Altadill, A.; Rodriguez, M.; Gonzalez, L. O.; Junquera, S.; Corte, M. D.; Gonzalez-Dieguez, M. L.; Linares, A.; Barbon, E.; Fresno-Forcelledo, M.; Rodrigo, L.; et al. Liver expression of matrix metalloproteinases and their inhibitors in hepatocellular carcinoma. Dig. Liver Dis. 2009, 41, 740-748.
154. Tretiakova, M. S.; Hart, J.; Shabani-Rad, M. T.; Zhang, J.; Gao, Z. Distinction of Hepatocellular adenoma from hepatocellular carcinoma with and without cirrhosis using E-cadherin and matrix metalloproteinase. Mod. Pathol. 2009, 22, 1113-1120.
155. Gorrin Rivas, M. J. G.; Arii, S.; Furutani, M.; Harada, T.; Mizumoto, M.; Nishiyama, H.; Fujita, J.; Imamura, M. Expression of human macrophage metalloelastase gene in hepatocellular carcinoma: Correlation with angiostatin generation and its clinical significance. Hepatology 1998, 28, 986-993.
156. Nakatsukasa, H.; Ashida, K.; Higashi, T.; Ohguchi, S.; Tsuboi, S.; Hino, N.; Nouso, K.; Urabe, Y.; Kinugasa, N.; Yoshida, K.; et al. Cellular distribution of transcripts for tissue inhibitor of metalloproteinases 1 and 2 in human hepatocellular carcinomas. Hepatology 1996, 24, 82-88.
157. International Working Party. Terminology of nodular hepatocellular lesions. Hepatology 1995, 22, 983-993.
158. Korkaya, H.; Liu, S.; Wicha, M. S. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J. Clin. Invest. 2011, 121, 3804-3809.
159. McLean, K.; Gong, Y.; Choi, Y.; Deng, N.; Yang, K.; Bai, S.; Cabrera, L.; Keller, E.; McCauley, L.; Cho, K. R.; et al. Human ovarian carcinoma-associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production. J. Clin. Invest. 2011, 121, 3206-3219.
160. Yan, X.-L.; Jia, Y.-L.; Chen, L.; Zeng, Q.; Zhou, J.-N.; Fu, C.-J.; Chen, H.-X.; Yuan, H.-F.; Li, Z.-W.; Shi, L.; et al. Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: Role of the S100A4-mIR155-SOCS1-MMP-9 axis. Hepatology 2013, 57, 2274-2286.
161. Roderfeld, M.; Rath, T.; Lammert, F.; Dierkes, C.; Graf, J.; Roeb, E. Innovative immunohistochemistry identifies MMP-9 expressing macrophages at the invasive front of murine HCC. World J. Hepatol. 2010, 2, 175-179.
162. Tian, T.; Nan, K.; Guo, H.; Wang, W.; Ruan, Z.; Wang, S.; Liang, X.; Lu, C. PTEN inhibits the migration and invasion of HepG2 cells by coordinately decreasing MMP expression via the PI3K/Akt pathway. Oncol. Rep. 2010, 23, 1593-1600.
163. Park, S. Y.; Jeong, K. J.; Panupinthu, N.; Yu, S.; Lee, J.; Han, J. V. V.; Kim, J. M.; Lee, J. S.; Kang, J.; Park, C. G.; et al. Lysophospatidic-acid augments human hepatocellular carcinoma cell invasion through LPA1 receptor and MMP-9 expression. Oncogene 2011, 30, 1351-1359.
164. Yang, X.; Wang, D.; Dong, W.; Song, Z.; Dou, K. Inhibition of Na(+)/H(+) exchanger 1 by 5-(N-ethyl-N-isopropyl) amiloride reduces hypoxia-induced hepatocellular carcinoma invasion and motility. Cancer Lett. 2010, 295, 198-204.
165. Kessenbrock, K.; Plaks, V.; Werb, Z. Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell 2010, 141, 52-67.
166. Murugan, R. S.; Vinothini, G.; Hara, Y.; Nagini, S. Black tea polyphenols target matrix metalloproteinases, RECK, proangiogenic molecules and histone deacetylase in a rat hepatocarcinogenesis model. Anticancer Res. 2009, 29, 2301-2305.
167. Stefanou, N.; Papanikolaou, V.; Fukukawa, Y.; Nakamura, Y.; Tsezou, A. Leptin as a critical regulator of hepatocellular carcinoma development through modulation of human telomerase reverse transcriptase. BMC Cancer 2010, 10, 442.
168. Chen, Y.; Boyartchuk, V.; Lewis, B. Differential roles of insulin-like growth factor receptor-and insulin receptor-mediated signaling in the phenotypes of hepatocellular carcinoma cells. Neoplasia 2009, 11, 835-845.
169. Shengbing, Z.; Feng, L. J.; Bin, W.; Lingyun, G.; Aimin, H. Expression of KISS-1 gene and its role in invasion and metastasis of human hepatocellular carcinoma. Anat. Rec. (Hoboken) 2009, 292, 1128-1134.
170. Martin, D. C.; Sanchez-Swatman, O. H.; Ho, A. T.; Inderdeo, D. S.; Tsao, M.; Khokha, R. Transgenic TIMP-1 inhibits simian virus 40 T antigen-induced hepatocarcinogenesis by impairment of hepatocellular proliferation and tumor angiogenesis. Lab. Invest. 1999, 79, 225-234.