Obesity and diabetes accelerate hepatocarcinogenesis via hepatocyte proliferation independent of NF-κB or Akt/mTORC1  

作　　者：Evi Arfianti Claire Z Larter Seungsoo Lee Vanessa Barn Geoffrey Haigh Matthew M.Yeh George NIoannou Narci C.Teoh Geoffrey C.Farrell 

机构地区：[1]Liver Research Group,Australian National University Medical School,The Canberra Hospital,Australian Capital Territory,Australia [2]Faculty of Medicine,Universitas Riau,Pekanbaru,Indonesia [3]Division of Gastroenterology,University of Washington,Seattle,Washington,United States [4]Department of Pathology,University of Washington,Seattle,Washington,United States

出　　处：《Journal of Clinical & Translational Research》2016年第1期27-38,共12页临床和转化研究

摘　　要：Background:There are strong links between obesity,diabetes and hepatocellular carcinoma(HCC),but molecular mechanisms remain unclear.Aim:We tested the proposed involvement of NF-κB,IL-6/STAT3 and Akt/mTORC1 before onset(at 3 months)and at onset(6 months)of accelerated hepatocarcinogenesis in DEN-injected obese and diabetic foz/foz compared to lean wildtype(Wt)mice,and also studied the hepatocyte proliferative response to DNA damage between the obese and lean lines.Methods:Male foz/foz and Wt littermates fed normal chow were DEN-injected(10mg/kg i.p.)at age 12-15 days.To test the effect of mTOR inhibitor on growth of dysplastic hepatocytes,a separate cohort of DEN-injected foz/foz mice was administered rapamycin(4 mg/kg body weight/day).Results:foz/foz mice developed obesity,hyperinsulinemia,diabetes,adipokine dysregulation and fatty liver,without increased serum or liver TNF-αor serum IL-6.All DEN-injected foz/foz mice developed HCC by 6 mths vs.0/10 lean Wt.At 3 mths,there were more dysplastic hepatocytes in DEN-injected foz/foz than Wt,with increased liver injury(serum ALT),hepatocyte apoptosis(M30-positive cells)and proliferation(cyclin D1,cyclin E,PCNA),but neither NF-κB nor STAT3 activation.foz/foz livers exhibited upregulation of DNA damage sensors ATM and ATR,with inadequate cell cycle checkpoint controls(CHK1,CHK2,p53,p21).Akt and mTORC1 were highly activated in livers from foz/foz vs.Wt mice.Despite such activation,rapamycin failed to reduce growth of dysplastic hepatocytes.Conclusions:Accelerated DEN-induced HCC in obese/diabetic mice is linked to enhanced growth of dysplastic hepatocytes that cannot be attributed to NF-κB or IL-6/STAT3 activation,nor to sustained mTORC1 activation.The critical mechanism for obesity-enhanced hepatocarcinogenesis lies in the disconnection between hepatocellular injury with DNA damage,and an unrestrained proliferative response.Relevance for patients:This study supports the epidemiological data linking obesity,diabetes and fatty liver disease with increased risk for de

关 键 词：ATAXIA-TELANGIECTASIA mutated GLUTATHIONE-S-TRANSFERASE pi RAPAMYCIN INTERLEUKIN-6 signal transducer and activator of transcription3 

分 类 号：R73[医药卫生—肿瘤]