Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most frequent and deadliest human cancers worldwide
We found progressive iNos induction in rat and mouse liver lesions, always at higher levels in the most aggressive models represented by hepatocellular carcinoma (HCC) of rats genetically susceptible to hepatocarcinogenesis and c-Myc–transforming growth factor-a (TGF-a) transgenic mice. inducible nitric oxide synthase (iNOS), inhibitor of kB kinase/nuclear factor-kB (NF-kB) and RAS/extracellular signal-regulated kinase (ERK) upregulation was significantly higher in HCC with poorer prognosis and positively correlated with tumor proliferation, genomic instability and microvascularization and negatively with apoptosis
nitric oxide (NO) overproduction, induced by elevated oxidative stress in c-Myc–TGF-a transgenic mice [18] and by Glyco-S-nitroso-N-acetyl penicillamine-2 (GS2) in HCC cell lines, triggers HaRAS and ERK upregulation, whereas iNOS inhibition by AG or short interfering RNA (siRNA) is associated with decreased Ha-RAS activation
Summary
Hepatocellular carcinoma (HCC) is one of the most frequent and deadliest human cancers worldwide. Dysplastic nodules and HCC induced in susceptible Fisher 344 (F344) rats show upregulation of c-Myc, Cyclin D1, E and A and E2f1 genes, increased cyclin D1–Cdk, cyclin E–Cdk and E2f1–Dp1 complexes and retinoblastoma protein (pRb) hyperphosphorylation [4,5,6] These changes are absent or less pronounced in liver lesions from resistant Brown Norway (BN) rats, where a block of G1–S transition occurs. Alterations similar to those of F344 rats occur in aggressive HCCs from c-Myc–transforming growth factor-a (TGF-a) double-transgenic mice [7] and human hepatocellular carcinoma with poorer prognosis (HCCP) [8], whereas the expression patterns in HCCs from BN rats roughly resemble those of human hepatocellular carcinoma with better prognosis (HCCB) This suggests that the basic mechanisms of hepatocarcinogenesis are similar in rodents and humans [4,7]
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