Carcinogenesis Advance Access originally published online on June 25, 2008
Carcinogenesis 2008 29(8):1639-1647; doi:10.1093/carcin/bgn155
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Aberrant iNOS signaling is under genetic control in rodent liver cancer and potentially prognostic for the human disease
Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy
* To whom correspondence should be addressed. Tel: +39 070228307; Fax: +39 070228485; Email: 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 Fisher 344 and Brown Norway rats, possessing different genetic predisposition to HCC, in transforming growth factor-
(TGF-) and c-Myc–TGF- transgenic mice, characterized by different susceptibility to HCC, and in human HCC: (i) iNOS function and interactions with nuclear factor-kB (NF-kB) and Ha-RAS/extracellular signal-regulated kinase (ERK) during hepatocarcinogenesis; (ii) influence of genetic predisposition to liver cancer on these pathways and role of these cascades in determining a susceptible or resistant phenotype and (iii) 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- transgenic mice. iNOS, inhibitor of kB kinase/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 short interfering RNA (siRNA) or ERK signaling by UO126 caused iNOS downregulation in HCC cell lines. These findings indicate that iNOS cross talk 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.
Abbreviations: AG, aminoguanidine; BN, Brown Norway; ERK, extracellular signal-regulated kinase; F344, Fisher 344; GS2, Glyco-SNAP-2; GTP, guanosine triphosphate; HCC, hepatocellular carcinoma; HCCB, hepatocellular carcinoma with better prognosis; HCCP, hepatocellular carcinoma with poorer prognosis; IFN-
, interferon-; IKB, inhibitor of kB; IKK, inhibitor of kB kinase; IL, interleukin; iNOS, inducible nitric oxide synthase; mRNA, messenger RNA; MVD, microvessel density; NF-kB, nuclear factor-kB; NO•, nitric oxide; pRb, retinoblastoma protein; siRNA, short interfering RNA; SL, surrounding liver; Sulfa, sulfasalazine; TGF-, transforming growth factor-; TNF-, tumor necrosis factor-
Received March 28, 2008; revised May 19, 2008; accepted June 17, 2008.
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