Abstract
There are strong links between obesity, diabetes and hepatocellular carcinoma (HCC), but molecular mechanisms remain unclear. 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. 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). foz/foz mice developed obesity, hyperinsulinemia, diabetes, adipokine dysregulation and fatty liver, without increased serum or liver TNF-α or 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. 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. 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.
Highlights
Obesity increases hepatocellular carcinoma (HCC) risk up to 4-fold [1,2,3], but the molecular pathways driving such promotion of hepatocarcinogenesis remain unclear
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/signal transducer and activator of transcription 3 (STAT3) activation, nor to sustained mammalian target of rapamycin complex 1 (mTORC1) activation
We used mice defective for the non-homologous end joining pathway of DNA strand break repair, Ku70-/- mice, to show how DEN injection caused chromosomal instability (CIN), with resultant loss of p53 function that facilitated accelerated onset of hepatocarcinogenesis [18]. These findings indicate that cellular responses to DNA damage, an expected consequence of oxidative stress in non-alcoholic steatohepatitis (NASH) or cirrhosis, cause CIN, which in turn contributes to the multistep process of hepatocarcinogenesis
Summary
Obesity increases hepatocellular carcinoma (HCC) risk up to 4-fold [1,2,3], but the molecular pathways driving such promotion of hepatocarcinogenesis remain unclear. While IL-6-dependent signaling plays a role in diethylnitrosamine (DEN)-induced HCC in lean mice, obesity is more likely to promote hepatocarcinogenesis by a different mechanism. Another potential link between obesity and HCC is hyperinsulinemia resulting from insulin resistance, which exerts growth effects either directly or via release of insulin-like growth factor-1 (IGF-1) [8,9]. MTOR inhibition by rapamycin increased liver injury, IL-6 release and signal transducer and activator of transcription 3 (STAT3) activation [15]. 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 studied the hepatocyte proliferative response to DNA damage between the obese and lean lines
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