- Email: [email protected]
TERT promoter and CTNNB1 gene mutations represent cancer signatures specific for hepatitis B and hepatitis C related hepatocellular carcinoma
Abstracts / Digestive and Liver Disease 49S (2017) e19–e42
T-19
T-20
Hypoxia-inducible factor 2␣ drives the progression of experimental non-alcoholic fatty liver disease by stimulating hepatocyte production of histidine rich glycoprotein
TERT promoter and CTNNB1 gene mutations represent cancer signatures specific for hepatitis B and hepatitis C related hepatocellular carcinoma
S. Sutti 1 , E. Morello 2 , S. Cannito 2 , E. Novo 2 , C. Bocca 2 , B. Foglia 2 , S. Bruzzì 3 , E. Bugianesi 1 , E. Albano 3 , M. Parola 2
F. Pezzuto 1 , F. Izzo 2 , L. Buonaguro 1 , C. Annunziata 1 , F. Tatangelo 3 , G. Botti 3 , F.M. Buonaguro 1 , M.L. Tornesello 1
1
1
Department Medical Sciences, University of Torino, Turin, Italy 2 Department Clinical and Biological Sciences, University of Torino, Turin, Italy 3 Department Health Sciences, A. Avogadro University, Novara, Italy Introduction: Hypoxia and hypoxia inducible factors (HIFs) are believed to significantly affect fibrogenic progression of chronic liver diseases (CLD). Recently, we showed that HIF-2␣ expression is up-regulated in parenchymal cells in either experimental or human non-alcoholic fatty liver disease (NAFLD) and contributes in sustaining liver fibrogenesis in the methionine/choline-deficient (MCD) diet model of NAFLD. Aims: In the present study, we provide further insides in the mechanisms by which HIF-2␣ promotes the progression of experimental NAFLD. Methods: NAFLD was induced by feeding in mice with hepatocyte-specific conditional deletion of HIF-2␣ (HIF-2␣ fl/fl/Alb-Cre mice) and control littermates with MCD and cholinedeficient l-amino acid refined (CDAA) diets. In vitro studies have been performed using HepG2 cells overexpressing HIF-2␣. Results: In both the dietary models of NAFLD hepatocyte deletion of HIF-2␣ resulted in: (i) a decrease in fatty liver and parenchymal necrosis; (ii) amelioration in lobular inflammation and in the hepatic expression of pro-inflammatory cyto/chemokines (TNF-␣, IL-12, CCL2, CXCL10); (iii) a significant decrease in the expression of pro-fibrogenic genes (collagen 1A1, TGF-1, ␣-SMA) as well as in extracellular matrix deposition (Sirius Red staining) and in the number of activated myofibroblasts. Such an improvement in NAFLD evolution in HIF-2␣ deficient mice was associated with a selective lowering of the hepatic production of Histidine-Rich Glycoprotein (HRGP), a hepatocyte-derived protein recently implicated in sustaining macrophage M1 activation. Accordingly, flow cytometry showed a decreased production of IL-12 by macrophages isolated from HIF-2␣ fl/fl/Alb-Cre mice receiving the MCD diet. Furthermore, in vitro experiments confirmed that up-regulation of HIF-2␣ resulted in enhanced HRGP expression by HepG2 cells. Conclusions: These results indicate that activation of HIF-2␣ in hepatocytes stimulates the progression of experimental NAFLD through the up-regulation of HRGP production. http://dx.doi.org/10.1016/j.dld.2017.01.057
e27
Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori “Fondazione G Pascale” – IRCCS, Napoli, Italy 2 Hepatobiliary Surgery Unit, Istituto Nazionale Tumori “Fondazione G Pascale” – IRCCS, Napoli, Italy 3 Department of Pathology, Istituto Nazionale Tumori “Fondazione G Pascale” – IRCCS, Napoli, Italy Introduction and aim: Recurrent somatic mutations in the promoter region of telomerase reverse transcriptase (TERT) gene and in the exon 3 of CTNNB1 gene have been recognized as common events in hepatocellular carcinoma (HCC) with variable frequencies depending on etiology and geographical region. We analyzed the distribution of such mutations in a cohort of hepatitis B (HBV) and hepatitis C (HCV) related HCC patients from Southern Italy. Materials and methods: Our cohort consisted of 122 cases of hepatitis B (HBV) and hepatitis C (HCV) related HCCs and 7 cases of cholangiocarcinoma and hepatocholangiocarcinoma (CC/HCC-CC). TERT promoter and CTNNB1 gene mutations were searched in all tumor biopsies and in autologous cirrhotic tissues. Results: Overall, 50.4% and 26% of HCC as well as 14.3% and none of CC/HCC-CC were mutated in TERT promoter and in CTNNB1 exon 3, respectively. TERT and CTNNB1 mutations were found more frequently in HCV related (53.6% and 26.4%, respectively) than HBV related (41.7% and 16.7%, respectively) HCCs and coexisted in 57.6% of CTNNB1 mutated tumors. Mutations in TERT and CTNNB1 were not associated with the functional promoter polymorphism rs2853669. No mutations were detected in the 129 non-HCC cirrhotic tissues. Conclusions: Mutations in TERT promoter and in CTNNB1 gene represent specific cancer signatures in the pathogenesis of viral related HCC and could be promising early biomarkers as well as targets for tailored therapies. http://dx.doi.org/10.1016/j.dld.2017.01.058
T-19
T-20
Hypoxia-inducible factor 2␣ drives the progression of experimental non-alcoholic fatty liver disease by stimulating hepatocyte production of histidine rich glycoprotein
TERT promoter and CTNNB1 gene mutations represent cancer signatures specific for hepatitis B and hepatitis C related hepatocellular carcinoma
S. Sutti 1 , E. Morello 2 , S. Cannito 2 , E. Novo 2 , C. Bocca 2 , B. Foglia 2 , S. Bruzzì 3 , E. Bugianesi 1 , E. Albano 3 , M. Parola 2
F. Pezzuto 1 , F. Izzo 2 , L. Buonaguro 1 , C. Annunziata 1 , F. Tatangelo 3 , G. Botti 3 , F.M. Buonaguro 1 , M.L. Tornesello 1
1
1
Department Medical Sciences, University of Torino, Turin, Italy 2 Department Clinical and Biological Sciences, University of Torino, Turin, Italy 3 Department Health Sciences, A. Avogadro University, Novara, Italy Introduction: Hypoxia and hypoxia inducible factors (HIFs) are believed to significantly affect fibrogenic progression of chronic liver diseases (CLD). Recently, we showed that HIF-2␣ expression is up-regulated in parenchymal cells in either experimental or human non-alcoholic fatty liver disease (NAFLD) and contributes in sustaining liver fibrogenesis in the methionine/choline-deficient (MCD) diet model of NAFLD. Aims: In the present study, we provide further insides in the mechanisms by which HIF-2␣ promotes the progression of experimental NAFLD. Methods: NAFLD was induced by feeding in mice with hepatocyte-specific conditional deletion of HIF-2␣ (HIF-2␣ fl/fl/Alb-Cre mice) and control littermates with MCD and cholinedeficient l-amino acid refined (CDAA) diets. In vitro studies have been performed using HepG2 cells overexpressing HIF-2␣. Results: In both the dietary models of NAFLD hepatocyte deletion of HIF-2␣ resulted in: (i) a decrease in fatty liver and parenchymal necrosis; (ii) amelioration in lobular inflammation and in the hepatic expression of pro-inflammatory cyto/chemokines (TNF-␣, IL-12, CCL2, CXCL10); (iii) a significant decrease in the expression of pro-fibrogenic genes (collagen 1A1, TGF-1, ␣-SMA) as well as in extracellular matrix deposition (Sirius Red staining) and in the number of activated myofibroblasts. Such an improvement in NAFLD evolution in HIF-2␣ deficient mice was associated with a selective lowering of the hepatic production of Histidine-Rich Glycoprotein (HRGP), a hepatocyte-derived protein recently implicated in sustaining macrophage M1 activation. Accordingly, flow cytometry showed a decreased production of IL-12 by macrophages isolated from HIF-2␣ fl/fl/Alb-Cre mice receiving the MCD diet. Furthermore, in vitro experiments confirmed that up-regulation of HIF-2␣ resulted in enhanced HRGP expression by HepG2 cells. Conclusions: These results indicate that activation of HIF-2␣ in hepatocytes stimulates the progression of experimental NAFLD through the up-regulation of HRGP production. http://dx.doi.org/10.1016/j.dld.2017.01.057
e27
Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori “Fondazione G Pascale” – IRCCS, Napoli, Italy 2 Hepatobiliary Surgery Unit, Istituto Nazionale Tumori “Fondazione G Pascale” – IRCCS, Napoli, Italy 3 Department of Pathology, Istituto Nazionale Tumori “Fondazione G Pascale” – IRCCS, Napoli, Italy Introduction and aim: Recurrent somatic mutations in the promoter region of telomerase reverse transcriptase (TERT) gene and in the exon 3 of CTNNB1 gene have been recognized as common events in hepatocellular carcinoma (HCC) with variable frequencies depending on etiology and geographical region. We analyzed the distribution of such mutations in a cohort of hepatitis B (HBV) and hepatitis C (HCV) related HCC patients from Southern Italy. Materials and methods: Our cohort consisted of 122 cases of hepatitis B (HBV) and hepatitis C (HCV) related HCCs and 7 cases of cholangiocarcinoma and hepatocholangiocarcinoma (CC/HCC-CC). TERT promoter and CTNNB1 gene mutations were searched in all tumor biopsies and in autologous cirrhotic tissues. Results: Overall, 50.4% and 26% of HCC as well as 14.3% and none of CC/HCC-CC were mutated in TERT promoter and in CTNNB1 exon 3, respectively. TERT and CTNNB1 mutations were found more frequently in HCV related (53.6% and 26.4%, respectively) than HBV related (41.7% and 16.7%, respectively) HCCs and coexisted in 57.6% of CTNNB1 mutated tumors. Mutations in TERT and CTNNB1 were not associated with the functional promoter polymorphism rs2853669. No mutations were detected in the 129 non-HCC cirrhotic tissues. Conclusions: Mutations in TERT promoter and in CTNNB1 gene represent specific cancer signatures in the pathogenesis of viral related HCC and could be promising early biomarkers as well as targets for tailored therapies. http://dx.doi.org/10.1016/j.dld.2017.01.058