Purpose: Alteration of liver function during pro- gression of hepatocellular carcinoma (HCC) and cirrhosis affects the serum glycoprotein pattern. In this study, the changes in the N-glycome in liver tis- sue from pat...Purpose: Alteration of liver function during pro- gression of hepatocellular carcinoma (HCC) and cirrhosis affects the serum glycoprotein pattern. In this study, the changes in the N-glycome in liver tis- sue from patients with hepatocellular carcinoma and cirrhosis caused by hepatitis B virus infection were investigated to find out the relationship between this maker and liver disease. Methods: Twenty patients, 11 with cirrhosis and 9 with hepatocellular carcinoma, and 15 healthy donors were involved in this study. Liver protein N-glycans were profiled using the DSA-FACE technique developed in our laboratory. To further analyze the fucosylation status of these liver glycans Western lectin blots of total liver proteins were performed using Aspergillus oryzae lectin (AOL) as probe, which is a carbohydrate- binding protein that recognizes specifically α-1,6-fu- cosylated glycans. Results: The N-glycome of liver proteins in patients with HBV related HCC and cirrhosis was analyzed. Compared with healthy donors, the N-glycome had significantly less (p < 0.05) high mannose (M8) in both groups of patients. The total core α-1,6-fucosy-lation in total liver glycoproteins was dramatically increased during the progress of hepatocellular carcinoma and cirrhosis compared to the controls. Conclusion: These results show that fucosylation not only increases in serum proteins but also in liver tissue itself of patients with HBV related HCC and cirrhosis.展开更多
Histone deacetylase 1(HDAC1)is an important epigenetic controller involvedin transcriptional regulation throughmodification of chromatin structure.Genetic and epigenetic changes and deregulation of signal transduction...Histone deacetylase 1(HDAC1)is an important epigenetic controller involvedin transcriptional regulation throughmodification of chromatin structure.Genetic and epigenetic changes and deregulation of signal transduction pathways have been implicated in the development of breast cancer.Downregulation of estrogen receptor a(ERa)expression is one of the mechanisms behind the acquisition of endocrine resistance.Sustained and increased hormone and growth factor receptor signaling in breast cancer cells contribute to resistance to endocrine therapy.Both HDACs and the PI3K/mTOR signaling pathway are becoming promising targets in breast cancer,reversing also acquired hormone resistance.Here we show how mitogens,activating the PI3K/mTOR pathway,trigger the phosphorylation of HDAC1 in breast cancer cells,which is completely dependent on the activity of the p70 S6 kinase(S6K1).Our findings show that S6K1,overexpressed in many breast cancers,controls HDAC1-dependent transcriptional regulation of ERa levels upon mitogenic stimuli,controlling HDAC1 recruitment to the ERa promoter.Furthermore,cell treatment with both mTOR and HDACs inhibitors shows an additive effect in inhibiting breast cancer proliferation.This confirms the novel cross-talk between the HDAC1 and PI3K pathways with clinical implications towards the treatment of this malignant disease.展开更多
文摘Purpose: Alteration of liver function during pro- gression of hepatocellular carcinoma (HCC) and cirrhosis affects the serum glycoprotein pattern. In this study, the changes in the N-glycome in liver tis- sue from patients with hepatocellular carcinoma and cirrhosis caused by hepatitis B virus infection were investigated to find out the relationship between this maker and liver disease. Methods: Twenty patients, 11 with cirrhosis and 9 with hepatocellular carcinoma, and 15 healthy donors were involved in this study. Liver protein N-glycans were profiled using the DSA-FACE technique developed in our laboratory. To further analyze the fucosylation status of these liver glycans Western lectin blots of total liver proteins were performed using Aspergillus oryzae lectin (AOL) as probe, which is a carbohydrate- binding protein that recognizes specifically α-1,6-fu- cosylated glycans. Results: The N-glycome of liver proteins in patients with HBV related HCC and cirrhosis was analyzed. Compared with healthy donors, the N-glycome had significantly less (p < 0.05) high mannose (M8) in both groups of patients. The total core α-1,6-fucosy-lation in total liver glycoproteins was dramatically increased during the progress of hepatocellular carcinoma and cirrhosis compared to the controls. Conclusion: These results show that fucosylation not only increases in serum proteins but also in liver tissue itself of patients with HBV related HCC and cirrhosis.
基金This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro to S.C.(AIRC IG5732,AIRC IG12075)S.Ci.was supported by a fellowship from Fondazione Umberto Veronesi(FUV).
文摘Histone deacetylase 1(HDAC1)is an important epigenetic controller involvedin transcriptional regulation throughmodification of chromatin structure.Genetic and epigenetic changes and deregulation of signal transduction pathways have been implicated in the development of breast cancer.Downregulation of estrogen receptor a(ERa)expression is one of the mechanisms behind the acquisition of endocrine resistance.Sustained and increased hormone and growth factor receptor signaling in breast cancer cells contribute to resistance to endocrine therapy.Both HDACs and the PI3K/mTOR signaling pathway are becoming promising targets in breast cancer,reversing also acquired hormone resistance.Here we show how mitogens,activating the PI3K/mTOR pathway,trigger the phosphorylation of HDAC1 in breast cancer cells,which is completely dependent on the activity of the p70 S6 kinase(S6K1).Our findings show that S6K1,overexpressed in many breast cancers,controls HDAC1-dependent transcriptional regulation of ERa levels upon mitogenic stimuli,controlling HDAC1 recruitment to the ERa promoter.Furthermore,cell treatment with both mTOR and HDACs inhibitors shows an additive effect in inhibiting breast cancer proliferation.This confirms the novel cross-talk between the HDAC1 and PI3K pathways with clinical implications towards the treatment of this malignant disease.
