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Carcinogenesis Advance Access published online on June 25, 2008
Carcinogenesis, doi:10.1093/carcin/bgn155
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Aberrant iNOS signaling is under genetic control in rodent liver cancer and potentially prognostic for the human disease

Diego F. Calvisi, Federico Pinna, Sara Ladu, Rossella Pellegrino, Maria R. Muroni, Maria M. Simile, Maddalena Frau, Maria L. Tomasi, Maria R. De Miglio, Maria A. Seddaiu, Lucia Daino, Valeria Sanna, Francesco Feo and Rosa M. Pascale

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

Correspondence: Francesco Feo, MD. Dipartimento di Scienze Biomediche, Sezione di Patologia Sperimentale e Oncologia. Università di Sassari (Italy). Tel. +39-070228307; Fax: +39-228485; e-mail: feo{at}uniss.it

Mounting evidence underlines the role of inducible nitric oxide synthase (iNOS) in hepatocellular carcinoma (HCC) development, but its functional interactions with pathways involved in HCC progression remain uninvestigated. Here, we analyzed in preneoplastic and neoplastic livers from F344 and BN rats, possessing different genetic predisposition to HCC, in TGF-{alpha} and c-Myc-TGF-{alpha} transgenic mice, characterized by different susceptibility to HCC, and in human HCC: (a) iNos function and interactions with nuclear factor kB (NF-kB) and Ha-RAS/ERK during hepatocarcinogenesis; (b) influence of genetic predisposition to liver cancer on these pathways, and role of these cascades in determining a susceptible or resistant phenotype; (c) iNOS prognostic value in human HCC. We found progressive iNos induction in rat and mouse liver lesions, always at higher levels in the most aggressive models represented by HCC of rats genetically susceptible to hepatocarcinogenesis and c-Myc-TGF-{alpha} transgenic mice. iNOS, IKK/NF-kB, and RAS/ERK upregulation was significantly higher in HCC with poorer prognosis (as defined by patients’ survival length) and positively correlated with tumor proliferation, genomic instability and microvascularization, and negatively with apoptosis. Suppression of iNOS signaling by Aminoguanidine led to decreased HCC growth and NF-kB and RAS/ERK expression, and increased apoptosis both in vivo and in vitro. Conversely, block of NF-kB signaling by Sulfasalazine or siRNA, or ERK signaling by UO126 caused iNOS downregulation in HCC cell lines. These findings indicate that iNOS crosstalk with NF-kB and Ha-RAS/ERK cascades influences HCC growth and prognosis, suggesting that key component of iNOS signaling could represent important therapeutic targets for human HCC.

Key Words: iNOS • hepatocarcinogenesis • signal transduction • transgenic mice • prognosis • human HCC

Received March 28, 2008; revised May 19, 2008; accepted June 17, 2008.


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