Obesity and hepatocellular carcinoma

Caldwell, Stephen H.; Crespo, Déborah; Kang, Hyon S.; Al‐Osaimi, Abdullah

doi:10.1053/j.gastro.2004.09.021

Cited by 366 publications

(274 citation statements)

References 43 publications

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“…HCC is thought to occur in response to chronic liver injury, which may drive compensatory hyperproliferation of transformed hepatocytes [2]. Chronic liver injury can result from alcohol consumption, viral infection or the progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic hepatosteatitis (NASH) [3]. In agreement with this, epidemiological observations have revealed a link between high-fat diet feeding/obesity and the risk of HCC.…”

Section: Introductionmentioning

confidence: 89%

Oleate-mediated activation of phospholipase D and mammalian target of rapamycin (mTOR) regulates proliferation and rapamycin sensitivity of hepatocarcinoma cells

2011

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Aims/hypothesis A high-fat diet and obesity are associated with increased risk of liver cancer. Because increased delivery of NEFA to the liver occurs in these conditions, we investigated the involvement of the unsaturated fatty acid oleate in hepatocarcinoma cell proliferation using humanderived hepatocarcinoma cell lines as model systems. Methods Western blotting, FACS analysis and [ 3 H]thymidine incorporation were used to study the signalling pathways and the proliferation of cells cultured for up to 72 h with or without a concentration of oleate considered to be relevant to human pathophysiology (50 μmol/l) or a concentration considered elevated (1 mmol/l). Results In HepG2 cells, proliferation was increased in the presence of 50 μmol/l oleate, but was decreased at 1 mmol/ l. This differential effect was correlated with the activation of the mammalian target of rapamycin complex 1 (mTORC1) and with increased translation of cell cycle regulators. Oleate-mediated mTORC1 activation required phospholipase D activation, which produces phosphatidic acid and is known to render mTORC1 rapamycin resistant.Remarkably, rapamycin resistance was found to affect specifically the mTORC1/eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) branch of the mTORC1 pathway in the presence of 50 μmol/l oleate. Furthermore, inhibition of phosphatidic acid production abolished oleateinduced increases in mTORC1 activity and cyclin A production. Importantly, the same differential effects of oleate on mTORC1 activation, cell cycle regulators and rapamycin resistance were found in SK-Hep1 cells. Conclusions/interpretation Oleate stimulates mTORC1 activation and rapamycin resistance. We propose that rapamycin-derived mTOR inhibitors are likely to be of limited therapeutic use to restrain hepatic tumour growth, particularly in the context of associated obesity.

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Section: Introductionmentioning

confidence: 89%

Oleate-mediated activation of phospholipase D and mammalian target of rapamycin (mTOR) regulates proliferation and rapamycin sensitivity of hepatocarcinoma cells

2011

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“…39 The mechanism of this association is proposed to be through the progression of nonalcoholic fatty liver disease. 49 …”

Section: Liver Cancermentioning

confidence: 99%

Cancer pattern among hypertensive patients in North Karelia, Finland

et al. 2005

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The objective of this study was to determine the sitespecific cancer incidence of hypertensive patients and examine the effect of blood pressure-related variables on the risk of cancers with elevated incidence among the hypertensive patients. A record linkage study of Hypertension Register of the North Karelia Project and the Finnish Cancer Registry was conducted. The mean follow-up time was 16 years. A total of 20 529 hypertensive patients were studied. Main outcome measures were standardised incidence ratios and hazard ratios. The overall cancer incidence was close to that of the general population for both men and women. The incidence rate for the kidney cancer was significantly increased in hypertensive patients (standardised incidence ratio 1.34, 95% confidence interval (CI) 1.11-1.60), as well as incidence rates for cancers of pancreas (1.26, 1.02-1.54), and endometrium (1.22, 1.01-1.44) in hypertensive women. The incidence of lung cancer was significantly decreased (0.86, 0.77-0.95). The incidence of liver cancer was elevated with borderline significance (1.36, 0.99-1.82). In Cox regression models, the use of antihypertensive drugs at baseline was a significant predictor of kidney (hazard ratio for use of antihypertensive drugs 1.89, 95% CI 0.96-3.75) and pancreatic cancer (1.78, 0.99-3.22) in women but not in men. The incidence of endometrial cancer or liver cancer was not related to blood pressure levels or the use of antihypertensive drugs. In women, obesity was a significant predictor of cancers of the endometrium, kidney and liver. In conclusion, increased occurrence of some cancer types among hypertensive patients seem to be partly explained by obesity and the use of antihypertensive drugs.

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“…That HCC was among the most common of cancers worldwide could then be accounted for by the fact that HBV infection, the leading cause for HCC, is endemic in southeast Asia (Beasley et al, 1981), the most populous area in the world, as well as in sub-Saharan Africa. More recently, it has become apparent that obesity, with its accompanying problems of diabetes mellitus and nonalcoholic steatohepatitis (NASH), represents a growing addition to the causes of HCC (Marrero et al, 2002;Caldwell et al, 2004;El-Serag et al, 2004). Furthermore, evidence is accumulating that both diabetes and chronic alcoholism behave synergistically with HBV and HCV infections in the induction of HCC (Hassan et al, 2002).…”

Section: Introductionmentioning

confidence: 99%