ErbB receptors and BER pathways in human gastric tumours: molecular implication of oxidative stres.

Background: Deregulation and cross-talk of intracellular signals have been shown to be the driving forces in cancers. In this study, ErbB and BER pathways in neoplastic gastric tissues and cells, as a molecular signature for tumor progression, were investigated. Methods: ErbBs and BER molecular signaling genes and proteins were evaluated in the gastric carcinoma cell line AGS in basal condition and after single or combined treatments with H2O2, EGF and LY294002 and in primary gastric carcinoma tissues by RT-qPCR and Western blot. Results: Increased levels of pEGFR and pMAPK were detected in AGS cells after treatments with H2O2, although EGFR expression did not show any significant change. In addition, H2O2 treatment downregulated pAKT, as compared to control or EGF-treated cells. PARP-1 expression was decreased after H2O2 treatment, while OGG1 protein and gene expression decreased with LY294002 treatment, suggesting an Akt-dependent mechanism. An upregulation of ErbB2 gene expression was observed after EGF treatment, while ErbB4 expression increased with H2O2 and LY294002. Nrf2 and APE1 gene expression levels were reduced by H2O2 and LY294002 combined treatments. Data on gastric tissues showed that EGFR, highly expressed in intestinal-type, diffuse-type gastric carcinomas and their normal counterparts, was not phosphorylated in all cases. In contrast, diffuse-type carcinomas showed increased pMAPK, pAKT and OGG1 expression, as compared to control tissues. ErbB2 and Mutyh gene expression levels were higher in intestinal-type than in diffuse-type carcinomas, while ErbB4 showed an opposite expression pattern. Conclusions: These data indicate that oxidative stress modify EGFR and BER signaling, suggesting an integrated role between these pathways.