Skip to main content
SpringerLink
Log in

Prognostic Significance of iNOS in Hepatocellular Carcinoma

  • Chapter
  • First Online:
Nitric Oxide (NO) and Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Epidemiological research indicates a contribution of chronic inflammatory liver diseases to development of hepatocellular carcinoma (HCC). Mounting evidence shows a carcinogenic role of NO• produced by inflammatory or cancer cells. The calcium-independent inducible isoform, iNOS, produces under inflammatory stimulation large amounts of NO• through the conversion of l-arginine to l-citrulline. NO• and NO•-derived oxidants can oxidize biomolecules, causing DNA damage. NO• interferes with the oxidative metabolism at different levels. It upregulates the AMP-activated protein kinase, thus switching off the ATP-consuming pathways such as lipogenesis or gluconeogenesis, while switching on the ATP-producing pathways such as fatty acid and glucose oxidation. Moreover, increase in mitochondrial NO• above physiological levels affects the oxygen-binding site of cytochrome c oxidase and induces pyruvate dehydrogenase kinase-1, an inhibitor of pyruvate dehydrogenase complex, thus inhibiting electron transport and oxygen consumption. NO• may also interact with different signaling pathways in hepatocarcinogenesis, including COX2, inhibitor of κB kinase (IKK)/nuclear factor B (NF-κB), and RAS/extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling. NO• stimulates COX-2 activity, and COX-2 inhibitors block NO• production in HCC cells. Furthermore, NO• and its derivatives may influence prostaglandin production by inducing lipid peroxidation and arachidonic acid release from cell membranes. Stimulation of EP2 receptor by PGE2 induces the association of the α subunit of the regulator G protein signaling and AXIN. This leads to the inactivation of glycogen synthase kinase-3β (GSK-3β) with consequent nuclear accumulation of β-catenin and increase in its transcriptional targets, c-Myc, c-Jun, and cyclin D1. PGE2 can also stimulate cell growth through the activation of several tyrosine kinase receptors, including EGFR and the PI3K/Akt pathways. Recent research on the interplay between iNOS and IKK/NF-κB and RAS/ERK pathways in HCC showed that these interactions are highest in the highly aggressive preneoplastic and neoplastic liver lesions of genetically susceptible rats and c-Myc/Tgf-α transgenic mice. The determination of iNOS expression in human HCC showed highest values in a subtype with poorer prognosis. Interestingly, iNOS levels are directly correlated with genomic instability, proliferation rate, and microvessel density of human HCC and inversely correlated with apoptosis and patients’ survival. These observations suggest that iNOS upregulation and changes in iNOS/NF-κB and iNOS/H-RAS/ERK cross talks are prognostic markers for HCC. Moreover, the block of iNOS signaling by a specific inhibitor such as aminoguanidine leads to a consistent decrease in HCC growth in c-Myc/TGF-α transgenic mice, decrease in growth and increase in apoptosis in human HCC cell lines, suggesting that the key components of iNOS signaling could represent therapeutic targets.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Avila, M.A., Berasain, C., Torres, L., Martin-Duce, A., Corrales, F.J., Yang, H, Prieto, J., Lu, S.C., Cavalleria, J., Rodes, J., and Mato, J.M. (2000). Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. J. Hepatol. 33, 907–914.

    Article  PubMed  CAS  Google Scholar 

  • Beckman, J.S. and Koppenol, W.H. (1996). Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and the ugly. Am. J. Physiol. 271, C1424–C1437.

    PubMed  CAS  Google Scholar 

  • Biegon, A., Alvarado, M., Budinger, T.F., Grossman, R., Hensley, K., West, M.S., Kotake, Y., Ono, M., and Floyd, R.A. (2002). Region-selective effects of neuroinflammation and antioxidant treatment on peripheral benzodiazepine receptors and NMDA receptors in the rat brain. J. Neurochem. 82, 924–934.

    Article  PubMed  CAS  Google Scholar 

  • Briassouli, P., Chan, F., Savage, K., Reis-Filho, J.S., and Linardopoulos, S. (2007). Aurora-A regulation of nuclear factor-kappaB signaling by phosphorylation of IkappaBalpha. Cancer Res. 67, 1689–1695.

    Article  PubMed  CAS  Google Scholar 

  • Brown, G.C. (2001). Regulation of mitochondrial respiration by nitric oxide inhibition of cytochrome c oxidase. Biochim. Biophys. Acta. 1504, 46–57.

    Article  PubMed  CAS  Google Scholar 

  • Bruix, J., Boix, L., Sala, M., and Llovet, J.M. (2004). Focus on hepatocellular carcinoma. Cancer Cell 5, 215–219. [PMID: 15050913]

    Article  PubMed  CAS  Google Scholar 

  • Cai, J., Mao, Z., Hwang, J.J., and Lu, S.C. (1998). Differential expression of methionine adenosyltransferase genes influences the rate of growth of human hepatocellular carcinoma cells. Cancer Res. 58, 1444–1450.

    PubMed  CAS  Google Scholar 

  • Calvisi, D.F., Factor, V.M., Ladu, S., Conner, E.A., and Thorgeirsson, S.S. (2004a). Disruption of beta-catenin pathway or genomic instability define two distinct categories of liver cancer in transgenic mice. Gastroenterology 126, 1374–1386.

    Article  PubMed  CAS  Google Scholar 

  • Calvisi, D.F., Ladu, S., Hironaka, K., Factor, V.M., and Thorgeirsson, S.S. 2004b. Vitamin E down-modulates iNOS and NADPH oxidase in c-Myc/TGF-alpha transgenic mouse model of liver cancer. J. Hepatol. 41, 815–822.

    Article  PubMed  CAS  Google Scholar 

  • Calvisi, D.F., Pascale, R.M., and Feo, F. (2007a). Dissection of signal transduction pathways as a tool for the development of targeted therapies of hepatocellular carcinoma. Rev. Recent Clin. Trials. 2, 217–236.

    Article  PubMed  CAS  Google Scholar 

  • Calvisi, D.F., Pinna, F., Ladu, S., Pellegrino, R., Muroni, M.R., Simile, M.M., Frau, M., Tomasi, M.L., De Miglio, M.R., Seddaiu, M.A., Daino, L., Sanna, V., Feo, F., and Pascale, R.M. (2008a). Aberrant iNOS signaling is under genetic control in rodent liver cancer and potentially prognostic for the human disease. Carcinogenesis 29, 1639–1647.

    Article  PubMed  CAS  Google Scholar 

  • Calvisi, D.F., Pinna, F., Ladu, S., Pellegrino, R., Sanna, V., Sini, M., Daino, L., Simile, M.M., De Miglio, M.R., Frau, M., Tomasi, M.L., Seddaiu, M.A., Muroni, M.R., Feo, F., and Pascale, R.M. (2008b). Ras-driven proliferation and apoptosis signaling during rat liver carcinogenesis is under genetic control. Int. J. Cancer 123, 2057–2064.

    Article  PubMed  CAS  Google Scholar 

  • Calvisi, D.F., Pinna, F., Meloni, F., Ladu, S., Pellegrino, R., Sini, M., Daino, L., Simile, M.M., De Miglio, M.R., Virdis, P., Frau, M., Tomasi, M.L., Seddaiu, M.A., Muroni, M.R., Feo, F., and Pascale, R.M. (2008c). Dual-specificity phosphatase 1 ubiquitination in extracellular signal-regulated-kinase-mediated control of growth in human hepatocellular carcinoma. Cancer Res. 68, 4192–4200.

    Article  PubMed  CAS  Google Scholar 

  • Calvisi, D.F., Simile, M.M., Ladu, S., Pellegrino, R., De Murtas, V., Pinna, F., Tomasi, M.L., Frau, M., Virdis, P., De Miglio, M.R., Muroni, M.R., Pascale, R.M., and Feo, F. (2007b). Altered methionine metabolism and global DNA methylation in liver cancer: relationship with genomic instability and prognosis. Int. J. Cancer. 121, 2410–2420.

    Article  PubMed  CAS  Google Scholar 

  • Castellone, M.D., Teramoto, H., Williams, B.O., Druey, K.M., and Gutkind, J.S. (2005). Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science 310, 1504–1510.

    Article  PubMed  CAS  Google Scholar 

  • Chen, C., Pore, N., Behrooz, A., Ismail-Beigi, F., and Maity, A. (2001). Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J. Biol. Chem. 276, 9519–9525.

    CAS  Google Scholar 

  • Cianchi, F., Cortesini, C., Fantappiè, O., Tesserini, L., Sardi, I., Lasagna, N., Perna, F., Fabbroni, V., Di Felice, A., Perigli, G., Mozzanti, R., and Masini, E. (2004). Cyclooxygenase-2 activation mediates the proangiogenic effect of nitric oxide in colorectal cancer. Clin. Cancer Res. 10, 2694–2704. Clin. Chim. Acta. 296, 181–191.

    Article  PubMed  CAS  Google Scholar 

  • Danishpajooh, I.O., Gudi, T., Chen, Y., Kharitonov, V.G., Sharma, V.S., and Boss, G.R. (2001). Nitric oxide inhibits methionine synthase activity in vivo and disrupts carbon flow through the folate pathway. J. Biol. Chem. 276, 27296–27303.

    Article  PubMed  CAS  Google Scholar 

  • Demple, B. and Harrison, L. (1994). Repair of oxidative damage to DNA: enzymology and biology. Ann. Rev. Biochem. 63, 915–948.

    Article  PubMed  CAS  Google Scholar 

  • Denda, A., Kitayama, W., Kishida, H., Murata, N., Tamura, K., Kusuoka, O., Tsutsumi, M., Nishikawa, F., Kita, E., Nakae, D., Konishi, Y., and Kuniyasu, H. (2007). Expression of inducible nitric oxide (NO) synthase but not prevention by its gene ablation of hepatocarcinogenesis with fibrosis caused by a choline-deficient, L-amino acid defined diet in rats and mice. Nitric Oxide 16, 164–176.

    Article  PubMed  CAS  Google Scholar 

  • Du, Q., Park, K.S., Guo, Z., He, P., Nagashima, M., Shao, L., Sahai, R., Geller, D.A., and Hussain, S.P. (2006). Regulation of human nitric oxide synthase 2 expression by Wnt beta-catenin signaling. Cancer Res. 66, 7024–7031.

    Article  PubMed  CAS  Google Scholar 

  • Elstrom, R.L., Bauer, D.E., Buzzai, M., Karnauskas, R., Harris, M.H., Plas, D.R., Zhuang, H., Cinalli, R.M., Alav, A., Rudin, C.M., and Thompson, C.B. (2004). Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 64, 3892–3899.

    Article  PubMed  CAS  Google Scholar 

  • Fang, Y.Z., Yang, S., and Wu, G. (2002). Free radicals, antioxidants, and nutrition. Nutrition 18, 872–879.

    Article  PubMed  CAS  Google Scholar 

  • Fantappié, O., Masini, E., Sardi, I., Raimondi, L., Bani, D., Solazzo, M., Vannacci, A., and Mazzanti, R. (2002). The MDR phenotype is associated with the expression of COX-2 and iNOS in a human hepatocellular carcinoma cell line. Hepatology 35, 843–852.

    Article  PubMed  CAS  Google Scholar 

  • Farazi, P.A. and DePinho, R.A. (2006). Hepatocellular carcinoma pathogenesis: from genes to environment. Nat. Rev. Cancer 6, 674–678.

    Article  PubMed  CAS  Google Scholar 

  • Favata, M.F., Horiuchi, K.Y., Manos, E.J., Daulerio, A.J., Stradley, D.A., Feeser, W.S., Van Dyk, D.E., Pitts, W.J., Earl, R.A., Hobbs, F., Copeland, R.A., Magolda, R.L., Scherle, P.A., and Trzaskos, J.M. (1998). Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem. 273, 18623–18632.

    Article  PubMed  CAS  Google Scholar 

  • Feitelson, M.A., Sun, B., Satiroglu Tufan, N.L., Liu, J., Pan, J., and Lian, Z. (2002). Genetic mechanisms of hepatocarcinogenesis. Oncogene 21, 2593–2604.

    Article  PubMed  CAS  Google Scholar 

  • Feo, F., Canuto, R.A., and Garcea, R. (1973). Acceptor control ratio of mitochondria. Factors affecting it in Morris hepatoma 5123 and Yoshida hepatoma AH-130. Eur. J. Cancer 9, 203–214.

    Article  PubMed  CAS  Google Scholar 

  • Feo, F., De Miglio, M.R., Simile, M.M., Muroni, M.R., Calvisi, D.F., Frau, M., and Pascale, R.M. (2006). Hepatocellular carcinoma as a complex polygenic disease. Interpretive analysis of recent developments on genetic predisposition. Biochim. Biophys. Acta. 1765, 126–167.

    CAS  Google Scholar 

  • Furuse, J. (2008). Growth factors as therapeutic targets in HCC. Crit. Rev. Oncol. Hematol. 67, 8–15.

    Article  PubMed  Google Scholar 

  • Garcea, R., Daino, L., Pascale, R.M., Simile, M.M., Puddu, M., Ruggii, M.E., Seddaiu, M.A., Satta, G., Sequenza, M.J., and Feo, F. (1989). Protooncogene methylation and expression in regenerating liver and preneoplastic liver nodules induced in the rat by diethylnitrosamine: effect of variations of S-adenosylmethionine:S-adenosylhomocysteine ratio. Carcinogenesis 10, 1183–1192.

    Article  PubMed  CAS  Google Scholar 

  • Ghoshal, A.K. (1995). New insight into the biochemical pathology of liver in choline deficiency. Crit. Rev. Biochem. Mol. Biol. 30, 263–273.

    Article  PubMed  CAS  Google Scholar 

  • Hagos, G.K., Carroll, R.E., Kouznetsova, T., Li, Q., Toader, V., Fernandez, P. A., Swanson, S.M., and Thatcher, G.R. (2007). Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo. Mol. Cancer Ther. 6, 2230–2239.

    Article  PubMed  CAS  Google Scholar 

  • Han, C., Michalopoulos, G., and Wu, T. (2006). Prostaglandin E2 receptor EP1 transactivates EGFR/Met receptor tyrosine kinases and enhances invasiveness in human hepatocellular carcinoma cells. J. Cell Physiol. 207, 261–270.

    Article  PubMed  CAS  Google Scholar 

  • Harris, A.L. (2002). Hypoxia – a key regulatory factor in tumour growth. Nat. Rev. Cancer 2, 38–47.

    Article  PubMed  CAS  Google Scholar 

  • Hoki, Y., Hiraku, Y., Ma, N., Murata, M., Matsumine, A., Nagahama, M., Shintani, K., Uchida, A., and Kawanishi, S. (2007). iNOS-dependent DNA damage in patients with malignant fibrous histiocytoma in relation to prognosis. Cancer Sci. 98, 163–168.

    Article  PubMed  CAS  Google Scholar 

  • Horton, R.A., Ceppi, E.D., Knowles, R.G., and Titheradge, M.A. (1994). Inhibition of hepatic gluconeogenesis by nitric oxide: a comparison with endotoxic shock. Biochem. J. 299, 735–739.

    PubMed  CAS  Google Scholar 

  • Huang, Z.-Z., Mao, Z., Cai, J., and Lu, S.C. (1998). Changes in methionine adenosyltransferase during liver regeneration. Am. J. Physiol. 38, G14–G21.

    Google Scholar 

  • Hung, W.C., Chuang, L.Y., Tsai, J.H., and Chang, C.C. (1993). Effects of epidermal growth factor on growth control and signal transduction pathways in different human hepatoma cell lines. Biochem. Mol. Biol. Int. 30, 319–328.

    Google Scholar 

  • Hussain, S.P. and Harris, C.C. (2006). p53 biological network: at the crossroads of the cellular-stress response pathway and molecular carcinogenesis. J. Nippon Med. Sch. 73, 54–64.

    Article  PubMed  CAS  Google Scholar 

  • Ikeguchi, M., Ueta, T., Yamane, Y., Hirooka, Y., and Kaibara, N. (2002). Inducible nitric oxide synthase and survivin messenger RNA expression in hepatocellular carcinoma. Clin. Cancer Res. 8, 3131–3136.

    PubMed  CAS  Google Scholar 

  • Iwai, S., Karim, R., Kitano, M., Sukata, T., Min, W., Morimura, K., Wanibuchi, H., Seki, S., and Fukushima, S. (2002). Role of oxidative DNA damage caused by carbon tetrachloride-induced liver injury- enhancement of MeIQ-induced glutathione S-transferase placental form-positive foci in rats. Cancer Lett. 179, 15–24.

    Article  PubMed  CAS  Google Scholar 

  • Jüngst, C., Cheng, B., Gehrke, R., Schmitz, V., Nischalke, H.D., Ramakers, J., Schramel, P., Schirmacher, P., Sauerbruch, T., and Caselmann, W.H. (2004). Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma. Hepatology 39, 1663–1672.

    Article  PubMed  CAS  Google Scholar 

  • Kanai, Y., Hui, A.M., Sun, L., Ushijima, S., Sakamoto, M., Tsuda, H., and Hirohashi, S. (1999). DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis, Hepatology 29, 703–709.

    Article  PubMed  CAS  Google Scholar 

  • Kawanishi, S., Hiraku, Y., Pinlaor, S., and Ma, N. (2006). Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis. Biol. Chem. 387, 365–372.

    Article  PubMed  CAS  Google Scholar 

  • Kim J.W. and Dang, C.V. (2006). Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res. 66, 8927–8930.

    Article  PubMed  CAS  Google Scholar 

  • Kim, J.W. and Dang, C.V. (2005). Multifaceted roles of glycolytic enzymes. Trends Biochem. Sci. 30, 142–150.

    Article  PubMed  CAS  Google Scholar 

  • Kim, Y.I., Pogribny, I.P., Basnakian, A.G., Miller, J.W., Selhub, J., James, S.J., and Mason, J. B. (1997). Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene. Am. J. Clin. Nutr. 65, 46–52.

    PubMed  CAS  Google Scholar 

  • Kong, G., Kim, E.K., Kim, W.S., Lee, K.T., Lee, Y.W., Lee, J.K., Paik, S.W., and Rhee, J.C. (2002). Role of cyclooxygenase-2 and inducible nitric oxide synthase in pancreatic cancer. J. Gastroenterol. Hepatol. 17, 914–921.

    Article  PubMed  CAS  Google Scholar 

  • Leary, S.C., Cobine, P.A., Kaufman, B.A., Guercin, G.H., Mattman, A., Palaty, J., Lockitch, G., Winge, D.R., Rustin, P., Horvath, R., and Shoubridge, E.A. (2007). The human cytochrome c oxidase assembly factors SCO1 and SCO2 have regulatory roles in the maintenance of cellular copper homeostasis. Cell Metab. 5, 9–20.

    Article  PubMed  CAS  Google Scholar 

  • Li, L.G. and Xu, H.M. (2005). Inducible nitric oxide synthase, nitrotyrosine and apoptosis in gastric adenocarcinomas and their correlation with a poor survival. World J. Gastroenterol. 11, 2539–2544.

    PubMed  CAS  Google Scholar 

  • Lu, S.C., Alvarez, L., Huang, Z.-Z., Chen, L., An, W., Corrales, F.J., Avila, M.T., Kanel, G., and Mato, J.M. (2002). Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation. Proc. Natl. Acad. Sci. USA 98, 5560–5565.

    Article  Google Scholar 

  • Majano, P.L., García-Monzón, C., García-Trevijano, E.R., Corrales, F.J., Cámara, J., Ortiz, P., Mato, J.M., Avila, M.A., and Moreno-Otero, R. (2001). S-adenosylmethionine modulates inducible nitric oxide synthase gene expression in rat liver and isolated hepatocytes. J. Hepatol. 35, 692–699.

    Article  PubMed  CAS  Google Scholar 

  • Martinez-Chantar, M.M.L., Garcıa-Trevijano, E.R., Latasa, M.U., Perez-Mmato, I., del Pino, M.M.S., Corrales, F.J., Avila, M.A., and Mato, J.M. (2002). Importance of a deficiency in S-adenosyl-L-methionine synthesis on the pathogenesis of liver injury. Am. J. Clin. Nutr. 76, 1177S–1182S.

    PubMed  CAS  Google Scholar 

  • Mato J.M., Corrales, F.J., Lu, S.C., and Avila, M.A. (2002). S-Adenosylmethionine: a control switch that regulates liver function. FASEB J. 16, 15–26.

    Article  PubMed  CAS  Google Scholar 

  • Misko, T.P., Moore, W.M., Kasten, T.P., Nickols, G.A., Corbett, J.A., Tilton, R.G., McDaniel, M.L., Williamson, J.R., and Currie, M.G. (1993). Selective inhibition of the inducible nitric oxide synthase by aminoguanidine. Eur. J. Pharmacol. 233, 119–125.

    Article  PubMed  CAS  Google Scholar 

  • Moncada, S., Palmer, R.M.J., and Higgs, E.A. (1991). Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol. Rev. 43, 109–142.

    PubMed  CAS  Google Scholar 

  • Monti, L.D., Valsecchi, G., Costa, S., Sandoli, E.P., Phan, C.V., Pontiroli, A.E., Pozza, G., and Piatti, P.M. (2000). Effects of endothelin-1 and nitric oxide on glucokinase activity in isolated rat hepatocytes. Metabolism 49, 73–80.

    Article  PubMed  CAS  Google Scholar 

  • Moriyama, A., Tabaru, A., Unoki, H., Abe, S., Masumoto, A., and Otsuki, M. (2000). Plasma nitrite/nitrate concentrations as a tumor marker for hepatocellular carcinoma. Clin. Chim. Acta. 296, 181–291.

    Article  PubMed  CAS  Google Scholar 

  • Nakano, H., Nakajima, A., Sakon-Komazawa, S., Piao, J.H., Xue, X., and Okumura, K. (2006). Reactive oxygen species mediate crosstalk between NF-kappaB and JNK. Cell Death Differ. 13, 730–737.

    Article  PubMed  CAS  Google Scholar 

  • Nisoli, E., Falcone, S., Tonello, C., Cozzi, V., Palomba, L., Fiorani, M., Pisconti, A., Brunelli, S., Cardile, A., Francolini, M., Cantoni, O., Carruba, M.O., Moncada, S., and Clementi, E. (2004). Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals. Proc. Natl. Acad. Sci. USA 101, 16507–16512.

    Article  PubMed  CAS  Google Scholar 

  • Ozel, E., Peştereli, H.E., Simşek, T., Erdoğan, G., and Karaveli, F.S. (2006). Expression of cyclooxygenase-2 and inducible nitric oxide synthase in ovarian surface epithelial carcinomas: is there any correlation with angiogenesis or clinicopathologic parameters? Int. J. Gynecl. Cancer 16, 549–555.

    Article  CAS  Google Scholar 

  • Pai, R., Soreghan, B., Szabo, I.L., Pavelka, M., Baatar, D., and Tarnawski, A.S. (2002). Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat. Med. 8, 289–293.

    Article  PubMed  CAS  Google Scholar 

  • Pannen, B.H. (2002). New insights into the regulation of hepatic blood flow after ischemia and reperfusion. Anesth. Analg. 94, 1448–1457.

    PubMed  CAS  Google Scholar 

  • Pascale, R.M., Marras, V., Simile, M.M., Daino, L., Pinna, G., Bennati, S., Carta, M., Seddaiu, M.A., Massarelli, G., and Feo, F. (1992). Chemoprevention of rat liver carcinogenesis by S-adenosyl-L-methionine: a long-term study. Cancer Res. 52, 4979–4986.

    PubMed  CAS  Google Scholar 

  • Pascale, R.M., Simile, M.M., Calvisi, D.F., Frau, M., Muroni, M.R., Seddaiu, M.A., Daino, L., Muntoni, M.D., De Miglio, M.R., Thorgeirsson, S.S., and Feo, F. (2005). Role of HSP90, CDC37, and CRM1 as modulators of P16 (INK4A) activity in rat liver carcinogenesis and and human liver cancer. Hepatology 42, 1310–1319.

    Article  PubMed  CAS  Google Scholar 

  • Pascale, R.M., Simile, M.M., De Miglio, M.R., Muroni, M.R., Calvisi, D.F., Asara, G., Casabona, D., Frau, M., Seddaiu, M.A., and Feo. F. (2002). Cell cycle deregulation in liver lesions of rats with and without genetic predisposition to hepatocarcinogenesis. Hepatology 35, 1341–1350.

    Article  PubMed  CAS  Google Scholar 

  • Pascale, R.M., Simile, M.M., Satta, G., Seddaiu, M.A., Daino, L., Pinna, G., Vinci, M.A., Gaspa, L., and Feo, F. (1991). Comparative effects of L-methionine, S-adenosyl-L-methionine and 5'-methylthioadenosine on the growth of preneoplastic lesions and DNA methylation in rat liver during the early stages of hepatocarcinogenesis. Anticancer Res. 11, 1617–1624.

    PubMed  CAS  Google Scholar 

  • Prudova, A., Bauman, Z., Braun, A., Vitvitsky, V., Lu, S.C., and Banerjee, R. (2006). S-adenosylmethionine stabilizes cystathionine beta-synthase and modulates redox capacity. Proc. Natl. Acad. Sci. USA 103, 6489–6494.

    Article  PubMed  CAS  Google Scholar 

  • Rahman, M.A., Dhar, D.K., Yamaguchi, E., Maruyama, S., Sato, T., Hayashi, H., Ono, T., Yamanoi, A., Kohno, H., and Nagasue, N. (2001). Coexpression of inducible nitric oxide synthase and COX-2 in hepatocellular carcinoma and surrounding liver: possible involvement of COX-2 in the angiogenesis of hepatitis C virus-positive cases. Clin. Cancer Res. 7, 1325–1332.

    PubMed  CAS  Google Scholar 

  • Rao, C.V., Indranie, C., Simi, B., Manning, P.T., Connor, J.R, and Reddy, B.S. (2002). Chemopreventive properties of a selective inducible nitric oxide synthase inhibitor in colon carcinogenesis, administered alone or in combination with celecoxib, a selective cyclooxygenase-2 inhibitor. Cancer Res. 62, 165–170.

    PubMed  CAS  Google Scholar 

  • Semenza, G.L. (2003). Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3, 721–732.

    Article  PubMed  CAS  Google Scholar 

  • Shen, J.C. Rideout III, W.M., and Jones, P.A. (1994). The rate of hydrolytic deamination of 5-methylcytosine in double-stranded DNA. Nucl. Acids Res. 25, 972–976.

    Article  Google Scholar 

  • Sheng, H., Shao, J., Washington, M.K., and DuBois, R.N. (2001). Prostaglandin E2 increases growth and motility of colorectal carcinoma cells. J. Biol. Chem. 276, 18075–18081.

    Article  PubMed  CAS  Google Scholar 

  • Shibutani, S., Takeshita, M., and Grollman, A.P. (1991). Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature 31(349), 431–434.

    Article  Google Scholar 

  • Simile, M.M., Pagnan, G., Pastorino, F., Brignole, C., De Miglio, M.R., Muroni, M.R., Asara, G., Frau, M., Seddaiu, M.A., Calvisi, D.F., Feo, F., Ponzoni, M., and Pascale, R.M. (2005). Chemopreventive N-(4-hydroxyphenyl)retinamide (fenretinide) targets deregulated NF-κB and Mat1A genes in the early stages of rat liver carcinogenesis. Carcinogenesis 26, 417–427.

    Article  PubMed  CAS  Google Scholar 

  • Sprangers, F., Sauerwein, H.P., Romijn, J.A., van Woerkom, G.M., and Meijer, A.J. (1998). Nitric oxide inhibits glycogen synthesis in isolated rat hepatocytes. Biochem. J. 330, 1045–1049.

    PubMed  CAS  Google Scholar 

  • Stadler, J., Barton, D., Beil-Moeller, H., Diekmann, S., Hierholzer, C., Erhard, W., and Heidecke, C.D. (1995). Hepatocyte nitric oxide biosynthesis inhibits glucose output and competes with urea synthesis for l-arginine. Am. J. Physiol. 268, G183–G188.

    PubMed  CAS  Google Scholar 

  • Stoner, G.D., Wang, L.S., and Chen, T. (2007). Chemoprevention of esophageal squamous cell carcinoma. Toxicol. Appl. Pharmacol. 224, 337–349.

    Article  PubMed  CAS  Google Scholar 

  • Sun, M.H. Han, X.C., Jia, M.K., Jiang, W.D., Wang, M., Zhang, H., Han, G., and Jiang, Y. (2005). Expressions of inducible nitric oxide synthase and matrix metalloproteinase-9 and their effects on angiogenesis and progression of hepatocellular carcinoma. World. J. Gastroenterol. 11, 5931–5937.

    PubMed  Google Scholar 

  • Tanaka, H., Yamamoto, M., Hashimoto, N., Miyakoshi, M., Tamakawa, S., Yoshie, M., Tokusashi, Y., Yokoyama, K., Yaginuma, Y., and Ogawa, K. (2006). Hypoxia-independent overexpression of hypoxia-inducible factor 1 alpha as an early change in mouse hepatocarcinogenesis. Cancer Res. 66, 11263–11270.

    Article  PubMed  CAS  Google Scholar 

  • Tanaka, Y., Hanada, K., Mizokami, M., Yeo, A.E., Shih, J.W., Gojobori, T., and Alter, H.J. (2002). A comparison of the molecular clock of hepatitis C virus in United States and Japan predicts that hepatocellular carcinoma incidence in United States will increase over the next two decades. Proc. Natl. Acad. Sci. USA 99, 15584–15589.

    Article  PubMed  CAS  Google Scholar 

  • Terranova, T., Feo, F., Gravela, E., and Gabiel, L. (1964). Die wirkung der 2-desoxyglucose auf den energetischen stoffwechsel und auf proteinsynthese von tunmorzellen und normalzellen. Zeit. Krebs. 66, 41–45.

    Article  CAS  Google Scholar 

  • Teufel, A., Staib, F., Kanzler, S., Weinmann, A., Schulze-Bergkamen, H., and Galle, P.R. (2007). Genetics of hepatocellular carcinoma. World J. Gastroenterol. 13, 2271–2282

    PubMed  CAS  Google Scholar 

  • Thorgeirsson, S.S. and Grisham, J.W. (2002). Molecular pathogenesis of human hepatocellular carcinoma. Nat. Genet. 31, 339–346.

    Article  PubMed  CAS  Google Scholar 

  • Veal, N., Hsieh, C.L., Xiong, S., Mato, J.M., Lu, S., and Tsukamoto, H. (2004). Inhibition of lipopolysaccharide-stimulated TNF-alpha promoter activity by S-adenosylmethionine and 5'-methylthioadenosine. Am. J. Physiol. Gastrointest. Liver Physiol. 287, G352–G362.

    Article  PubMed  CAS  Google Scholar 

  • Wainfan, E. and Poirier, L.A. (1992). Methyl groups in carcinogenesis: effects on DNA methylation and gene expression. Cancer Res 2, 2071s–77s.

    Google Scholar 

  • Warburg, O. (1956). On the origin of cancer cells. Science 123, 309–314.

    Article  PubMed  CAS  Google Scholar 

  • Weber, C.K., Liptay, S., Wirth, T., Adler, G., and Schmid, R.M. (2000). Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. Gastroenterology 119, 1209–1218.

    Article  PubMed  CAS  Google Scholar 

  • Weber, G., Kizaki, H., Shiotani, T., Tzeng, D. and Williams, J.C. (1977). The molecular correlation concept of neoplasia: recent advances and new challenges. Adv. Exp. Med. Biol. 92, 89–116.

    Article  PubMed  CAS  Google Scholar 

  • Weinberg, J.B. (2000). Nitric oxide synthase 2 and cyclooxygenase 2 interactions in inflammation. Immunol. Res. 22, 319–341.

    Article  PubMed  CAS  Google Scholar 

  • Wink, D.A., Ridnour, L.A., Perwez Hussain, S., and Harris, C.C. (2008). The reemergence of nitric oxide and cancer. Nitric Oxide 19, 65–67.

    Article  PubMed  CAS  Google Scholar 

  • Wu, G., Fang, Y.Z., Yang, S., Lupton, J.R., and Turner, N.D. (2004). Glutathione metabolism and its implications for health. J. Nutr. 134, 489–492.

    PubMed  CAS  Google Scholar 

  • Wu, G. and Morris, Jr. S.M. (1998). Arginine metabolism: nitric oxide and beyond. Biochem. J. 1336, 1–17.

    Google Scholar 

  • Wu, T. (2006). Cyclooxygenase-2 in hepatocellular carcinoma. Cancer Treat. Rev. 32, 28–44.

    Article  PubMed  CAS  Google Scholar 

  • Wu, X.Z., Xie, G.R., and Chen, D. (2007). Hypoxia and hepatocellular carcinoma: The therapeutic target for hepatocellular carcinoma. J. Gastroenterol. Hepatol. 22, 1178–1182.

    Article  PubMed  CAS  Google Scholar 

  • Yang, H. P., Sadda, M.R., Yu, V., Zeng, Y., Lee, T.D., Ou, X.P., Chen, L.X., and Lu, S.C. (2003). Induction of human methionine adenosyltransferase 2A expression by tumor necrosis factor a. Role of NF-κB and AP-1. J. Biol. Chem. 278, 50887–50896.

    Article  PubMed  CAS  Google Scholar 

  • Ying, L., Hofseth, A.B., Browning, D.D., Nagarkatti, M., Nagarkatti, P.S., and Hofseth, L.J. (2007). Nitric oxide inactivates the retinoblastoma pathway in chronic inflammation. Cancer Res. 67, 9286–9293.

    Article  PubMed  CAS  Google Scholar 

  • Zhang, J., Xie, Z., Dong, Y., Wang, S., Liu, C., and Zou, M.H. (2008). Identification of nitric oxide as an endogenous activator of the AMP-activated protein kinase in vascular endothelial cells. J. Biol. Chem. [Epub ahead of print]

    Google Scholar 

  • Zhang, J., Peng, B., and Chen, X. (2005). Expressions of nuclear factor kappaB, inducible nitric oxide synthase, and vascular endothelial growth factor in adenoid cystic carcinoma of salivary glands: correlations with the angiogenesis and clinical outcome. Clin. Cancer Res. 11, 7334–7343.

    Article  PubMed  CAS  Google Scholar 

  • Zingarelli, B., Hake, P.W., Yang, Z., O’Connor, M., Denenberg, A., and Wong, H.R. (2002). Absence of inducible nitric oxide synthase modulates early reperfusion-induced NF-kappaB and AP-1 activation and enhances myocardial damage. FASEB J. 16, 327–342

    Article  PubMed  CAS  Google Scholar 

  • Zou, M.H., Hou, X.Y., Shi, C.M., Kirkpatick, S., Liu, F., Goldman, M.H., and Cohen, R.A. (2003). Activation of 5 V-AMP-activated kinase is mediated through c-Src and phosphoinositide 3-kinase activity during hypoxia-reoxygenation of bovine aortic endothelial cells. Role of peroxynitrite. J. Biol. Chem. 278, 34003–34010.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Experimental Pathology and Oncology, Department of Biomedical Sciences, University of Sassari, Sassari, 07100, Italy

    Rosa M. Pascale

  2. Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy

    M. Frau

  3. Division of Experimental Pathology and Oncology, Department of Biomedical Sciences, University of Sassari, Sassari, 07100, Italy

    Francesco Feo

Authors
  1. Rosa M. Pascale
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Frau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesco Feo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesco Feo .

Editor information

Editors and Affiliations

  1. Dept. Microbiology, Immunology &, Molecular Genetics, University of California, Los Angeles, Charles E. Young Dr. E. 609, Los Angeles, 90095, California, USA

    Benjamin Bonavida

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science + Business Media, LLC

About this chapter

Cite this chapter

Pascale, R.M., Frau, M., Feo, F. (2010). Prognostic Significance of iNOS in Hepatocellular Carcinoma. In: Bonavida, B. (eds) Nitric Oxide (NO) and Cancer. Cancer Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1432-3_17

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-1432-3_17

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4419-1431-6

  • Online ISBN: 978-1-4419-1432-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation