| 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 |
| 3 | Non-severe burn injury increases cancer incidence in mice and has long-term impacts on the activation and function of T cells显示文摘Background:Recent evidence suggests that burn patients are at increased risk of hospital admission for infection,mental health conditions,cardiovascular disease and cancer for many years after discharge for the burn injury itself.Burn injury has also been shown to induce sustained immune system dysfunction.This change to immune function may contribute to the increased risk of chronic disease observed.However,the mechanisms that disrupt long-term immune function in response to burn trauma,and their link to long-term morbidity,remain unknown.In this study we investigated changes to immune function after burn injury using a murine model of non-severe injury.Methods:An established mouse model of non-severe burn injury(full thickness burn equivalent to 8%total body surface area)was used in combination with an orthotopic model of B16 melanoma to investigate the link between burns and cancer.Considering that CD8^(+)T cells are important drivers of effective tumour suppression in this model,we also investigated potential dysregulation of this immune population using mouse models of burn injury in combination with herpes simplex virus infection.Flow cytometry was used to detect and quantify cell populations of interest and changes in immune function.Results:We demonstrate that 4 weeks after a non-severe burn injury,mice were significantly more susceptible to tumour development than controls using an orthotopic model of B16 melanoma.In addition,our results reveal that CD8^(+)T cell expansion,differentiation and memory potential is significantly impaired at 1 month post-burn.Conclusions:Our data suggests that CD8^(+)T cell-mediated immunity may be dysfunctional for a sustained period after even non-severe burn injury.Further studies in patients to validate these findings may support clinical intervention to restore or protect immunity in patients after burn injury and reduce the increased risk of secondary morbidities observed. | Lucy W.Barrett Vanessa S.Fear Bree Foley Katherine Audsley Samantha Barnes Hannah Newnes Alison McDonnell Fiona M.Wood Mark W.Fear Jason Waithman | 2022 | Burns & Trauma2022，10，1： | 0 |
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