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| 1 | Obesity and diabetes accelerate hepatocarcinogenesis via hepatocyte proliferation independent of NF-κB or Akt/mTORC1显示文摘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 developing HCC.The findings also suggest that mTORC1 inhibition may not be beneficial in the prevention of obesity-related hepatocarcinogenesis. | Evi Arfianti Claire Z Larter Seungsoo Lee Vanessa Barn Geoffrey Haigh Matthew M.Yeh George NIoannou Narci C.Teoh Geoffrey C.Farrell | 2016 | Journal of Clinical & Translational Research2016，2，1： | 1 |
| 2 | Increased osteoblast adhesion on nanograined hydroxyapatite and partially stabilized zirconia composites显示文摘 | Evis Z Sato M Webster TJ | 2006 | J Biomed Mater Res A2006，78，3： | 1 |
| 3 | Ammonium exchange in leakage waters of waste dumps using natural zeolite from the Krapina region, Croatia显示文摘 | Farka? A Ro?i? M Miko?evi? Z B | 2005 | Journal of Hazardous Materials2005，117，1： | 1 |
| 4 | Complex regional pain syndrome type I in the upper extremity - how efficient physical therapy and rehabilitation are显示文摘 | Ze evi Lukovi T Ristl B Jovanov/Z | 2012 | Med Glas (Zeniea)2012，9，2： | 1 |
| 5 | Effects of cemented carbide surface pretreatment in combustion flame chemical vapour deposition of diamond显示文摘 | Marinkovié S Stankovié Z Rakoéevié | 1999 | Thin Solid Films1999，354，： | 1 |
| 6 | Internal quantum efficiency of Ⅲ-nitride quantum dot superlattices grown by plasmaassisted molecular-beam epitaxy显示文摘 | GA (C)EVI(C)(Z) DAS A TEUBERT J | 2011 | Journal of Applied Physics2011，109，10： | 1 |
| 7 | A review of 2D/3D registration methods for image-guided interventions显示文摘 | Markelj P Toma(z)evi(s) D Likar B | 2012 | Medical Image Analysis2012，16，3： | 1 |
| 8 | 查看详情显示文摘 | Evie L.P Marios B Vassilia Z Aleka M. Alexios P. Emmanuel S. Costas F | | 0，，07： | 1 |
| 9 | Personal learning environments on the Social Semantic Web显示文摘 | Jeremi Z Jovanovi J Ga evi D | 2013 | Semantic Web2013，4，1： | 1 |
| 10 | The effect of boron incorporation on the structure and properties of glassy carbon显示文摘 | Kalijadis A Jovanovi(c) Z Lau(s)evi(c) | | 0，，08： | 1 |
| 11 | Electrochemical determination of antioxidant capacity of fruit tea infusions显示文摘 | Piljac-(z)egarac J Valek L Stip(c)evi(c) T | 2010 | Food Chemistry2010，121，： | 1 |
| 12 | Polyphenol contents and antioxidant activity of Maydis stigma extracts 显示文摘 | MAKSIMOVI( Z MALEN(I( D KOVA(EVI( N | 2005 | Bioresource Technology2005，96，87： | 1 |
| 13 | Possibility of Rapid Determination of Low-Level 90Sr Activity by Combination of Extraction Chromatography Separation and Cherenkov Counting显示文摘 | Grahek Evi N Z Luli S | 1999 | Analytica Chimica Acta1999，399，3： | 1 |
| 14 | Topicsl azithromycin and clarithromycin inhibit acute and chronic skin inflammation in sensitized mice,with apparent selectivity for Th2-mediated processes in delayed-type hypersensitivity显示文摘 | Iveti(c)Tkal(c)evi(c)V Cu(z)i(c)S Dominis Kramati(c) M | | 0，，： | 1 |
| 15 | Immobilized lipases as practical catalysts显示文摘 | Kne(z)evi(c) Z D (S)iler-Marinkovi(c) S S Mojovi(c) L V | | 0，，： | 1 |
| 16 | Calcite Crystal Growth Kinetics in the Presence of Charged Synthetic Polypeptides显示文摘 | Njegi(c)-D(z)akula B Bre(c)evi(c) L Falini G | 2009 | Cryst Growth Des2009，9，： | 1 |
| 17 | Effects of initial supersaturation on spontaneous precipitation of calcium carbonate in the presence of charged poly-L-amino acids显示文摘 | Njegi(c)-D(z)akula B Falini G Bre(c)evi(c) L | 2010 | J Colloid Interf Sci2010，343，： | 1 |
| 18 | Characterization of trace metal particles deposited on some deciduous tree leaves in an urban area显示文摘 | TOMA?EVI?M VUKMIROVI?Z RAJ?I?S | 2005 | Chemosphere2005，61，6： | 1 |
| 19 | Hydroxyapatite and zirconia composites: Effect of MgO and MgF2 on the stability of phases and sinterability 显示文摘 | EVIS Z USTA M KUTBAY I | 2008 | Materials Chemistry and Physics2008，10，1： | 1 |
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