Aberrant iNOS signaling is under genetic control in rodent liver cancer and potentially prognostic for the human disease.
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-alpha (TGF-alpha) and c-Myc-TGF-alpha 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-alpha 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.
Calvisi
Diego F
DF
Department of Biomedical Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy.
Pinna
Federico
F
Ladu
Sara
S
Pellegrino
Rossella
R
Muroni
Maria R
MR
Simile
Maria M
MM
Frau
Maddalena
M
Tomasi
Maria L
ML
De Miglio
Maria R
MR
Seddaiu
Maria A
MA
Daino
Lucia
L
Sanna
Valeria
V
Feo
Francesco
F
Pascale
Rosa M
RM
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D008113:Liver Neoplasms / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D011379:Prognosis; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000502:physiology*
D052247:Nitric Oxide Synthase Type II