Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma

Chettouh, Hamza; Lequoy, Marie; Fartoux, Lætitia; Vigouroux, Corinne; Desbois-Mouthon, Christèle

doi:10.1111/liv.12903

Cited by 97 publications

(90 citation statements)

References 163 publications

(184 reference statements)

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“…In contrast to the lack of correlation with serum leptin, TNF-α, IL-6, NF-κB and STAT3 activation, hyperinsulinemia ( Figure 1D) in the foz/foz model remained a candidate enhancer of hepatocarcinogenesis [8,9]. In the present study, serum IGF-1 was higher, and serum IGF-binding protein (IGF-BP) 3 decreased in obese foz/foz compared to lean Wt, irrespective of DEN ( Figure 1L,M).…”

Section: Mtorc1 Signaling Is Activated In Livers and Hccs From Obese mentioning

confidence: 81%

“…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]. In hepatocytes, protein kinase B (Akt) and mammalian target of rapamycin complex 1 (mTORC1) are important mediators of insulin action [10,11]; ~ 40-50% of HCCs demonstrate Akt activation, and/or mTOR activation [12,13].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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-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. 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.

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Section: Mtorc1 Signaling Is Activated In Livers and Hccs From Obese mentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…Obesity and excessive visceral adipose tissue has been associated with a chronic inflammatory state due to increased levels of leptin. Leptin, a profibrotic and proangiogenic cytokine, activates the Janus kinase (JAK) pathway, thereby initiating an intracellular signaling cascade of pro-inflammatory cytokines[61,62]. Obesity has also been associated reduced level of adiponectin, an anti-inflammatory cytokine.…”

Section: Risk Factors and Proposed Mechanisms For Nash-related Hccmentioning

confidence: 99%

“…Diabetes has shown to be an independent risk factor for the development of HCC in NASH[61,63]. Excessive fat accumulation and obesity lead to hepatic and peripheral insulin resistance causing compensatory hyperinsulinemia.…”

Section: Risk Factors and Proposed Mechanisms For Nash-related Hccmentioning

confidence: 99%

Hepatocellular carcinoma in non-alcoholic steatohepatitis: Current knowledge and implications for management

Cholankeril

Patel

Khurana

et al. 2017

WJH

154

169

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With the prevalence of hepatitis C virus expected to decline, the proportion of hepatocellular carcinoma (HCC) related to non-alcoholic steatohepatitis (NASH) is anticipated to increase exponentially due to the growing epidemic of obesity and diabetes. The annual incidence rate of developing HCC in patients with NASH-related cirrhosis is not clearly understood with rates ranging from 2.6%-12.8%. While multiple new mechanisms have been implicated in the development of HCC in NASH; further prospective long-term studies are needed to validate these findings. Recent evidence has shown a significant proportion of patients with non-alcoholic fatty liver disease and NASH progress to HCC in the absence of cirrhosis. Liver resection and transplantation represent curative therapeutic options in select NASH-related HCC patients but have placed a significant burden to our healthcare resources and utilization. Currently NASH-related HCC is the fastest growing indication for liver transplant in HCC candidates. Increased efforts to implement effective screening and preventative strategies, particularly in non-cirrhotic NASH patients, are needed to reduce the future impact imposed by NASH-related HCC.

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“…Moreover, SOX17 plays a key role in regulating insulin secretion, as mice lacking Sox17 were more susceptible to high fat diet-induced hyperglycemia and diabetes [52]. Functionally, hyperinsulinaemia may affect HCC development not only through direct effects on the growth of hepatocytes, but also indirectly by increasing the production of cytokines and mitogens, enhancing fibrosis and promoting angiogenesis [53]. Taken together, down-regulation of SOX17 via promoter methylation may promote Wnt activity and insulin secretion and thereby accelerate the progression from NAFLD to HCC.…”

Section: Epigenetic Regulation Of Wnt/β-catenin Signaling In Nafldmentioning

confidence: 99%

Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis

Tian

Mok

Yang

et al. 2016

Cancers

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Non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in liver, is closely associated with central obesity, over-nutrition and other features of metabolic syndrome, which elevate the risk of developing hepatocellular carcinoma (HCC). The Wnt/β-catenin signaling pathway plays a significant role in the physiology and pathology of liver. Up to half of HCC patients have activation of Wnt/β-catenin signaling. However, the mutation frequencies of CTNNB1 (encoding β-catenin protein) or other antagonists targeting Wnt/β-catenin signaling are low in HCC patients, suggesting that genetic mutations are not the major factor driving abnormal β-catenin activities in HCC. Emerging evidence has demonstrated that obesity-induced metabolic pathways can deregulate chromatin modifiers such as histone deacetylase 8 to trigger undesired global epigenetic changes, thereby modifying gene expression program which contributes to oncogenic signaling. This review focuses on the aberrant epigenetic activation of Wnt/β-catenin in the development of NAFLD-associated HCC. A deeper understanding of the molecular mechanisms underlying such deregulation may shed light on the identification of novel druggable epigenetic targets for the prevention and/or treatment of HCC in obese and diabetic patients.

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Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma

Cited by 97 publications

References 163 publications

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

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

Hepatocellular carcinoma in non-alcoholic steatohepatitis: Current knowledge and implications for management

Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis

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