Walker, S.L, George, J., and Hebbard, L. (2011) Adiponectin loss is associated with increased hepatocellular growth via modulation of map kinase pathways and mammalian target of rapamycin. Journal of Gastroenterology and Hepatology, 26 (s4). p. 11.

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Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and the fastest growing incident cancer in Australia. Most HCCs appear in cirrhotic livers and it is known that overweight and obesity are independent risk factors for progression to cirrhosis and cancer. The mechanisms for this association are unclear. Adiponectin, a protein secreted by adipose tissue, is reduced in obesity and low levels are associated with progression of non-alcoholic steatohepatitis (NASH). The aim of our study was to investigate the role of adiponectin in a mouse model of HCC and its mechanism of action.

Methods Hepatocellular carcinoma was induced in adiponectin knockout and wild type mice using the chemical carcinogen, diethylnitrosamine (DEN), 25 mg/kg at 15 days of age. At 9 months after injection, mice from each genotype were euthanased, blood collected by cardiac puncture, livers dissected and assessed for tumour growth and weighed. Tumour incidence (>0.5 mm) and dimensions were measured and total tumour volume estimated. Paraffin embedded livers were sectioned and stained with haematoxylin and eosin and examined for pathology changes. Protein extracts from liver and tumour tissue were subjected to immunoblotting to examine signal transduction pathway changes. Total tissue mRNA was extracted to assess gene expression of key inflammatory mediators. Serum was prepared from whole blood and inflammatory cytokine levels measured by immunoassay.

Results Following DEN treatment, male adiponectin knockout mice developed liver tumours with 9 times greater tumour burden compared to wild type mice (adiponectin null 455 ± 199 mm3, n = 10; wild-type, 51 ± 26 mm3, n = 12; p = 0.0392). There was no quantitative difference in the tumour incidence between groups. Immunoblotting revealed that adiponectin deficiency was associated with altered MAPK, Akt and mTOR pathway activity in tumour tissue. There was no signifi cant difference in gene expression of IL-10, IL-6 or TNFα in tumour tissue detected by QPCR or by immunoassay of serum.

Conclusions Adiponectin null mice when exposed to hepatic carcinogens develop tumours that demonstrate a proliferative advantage. There was no difference in tumour expression of inflammatory mediators between adiponectin null and wild type mice. Adiponectin deficiency is associated with modulation of the MAP kinase cascades and the mTOR pathway in the tumours. These pathways may be potential targets for therapeutic intervention in patients with NASH-associated HCC.

Item ID:	86247
Item Type:	Article (Abstract)
ISSN:	1440-1746
Copyright Information:	© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.
Date Deposited:	22 Jul 2025 01:08
FoR Codes:	32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320209 Gastroenterology and hepatology @ 100%
SEO Codes:	20 HEALTH > 2001 Clinical health > 200101 Diagnosis of human diseases and conditions @ 100%
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