Walker, Sarah L., Deo, Nikita, George, Jacob, and Hebbard, Lionel (2012) The role of adiponectin in hepatocellular carcinoma: adiponectin loss is associated with a more aggressive phenotype. Journal of Gastroenterology and Hepatology, 27 (s4). pp. 14-15.

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Abstract

Background Hepatocellular carcinoma (HCC) is the fastest rising incident cancer in Australia. Most HCCs arise in cirrhotic livers but obesity is an independent risk factor for its development. In addition, obese patients have higher death rates from liver cancer. The mechanisms for this association are unknown. Adiponectin, a protein secreted by adipocytes, is reduced in obesity and low levels are associated with many common forms of cancer.

Aims 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 (ko) and wild type mice using diethylnitrosamine (DEN). At monthly intervals from 3 to 9 months after injection, mice were euthanased, blood collected, livers dissected and weighed. Tumour incidence (>0.5 mm) and dimensions were measured and tumour volume estimated. Paraffin embedded livers were sectioned and stained. Protein extracts from liver and tumour tissue were subjected to immunoblotting to examine signal transduction pathways. Total tissue mRNA was extracted to assess expression of key inflammatory mediators. Primary mouse tumour cells were cultured. Adiponectin ko and wild type derived HCC cells were characterised with regards to cell signalling and ability to form tumour spheres. Primary cultured HCC cells were subcutaneously injected into wild type mice and growth characteristics studied. The cells were treated with mTOR inhibitors: rapamycin, PP242 and BEZ235.

Results Following DEN treatment, male adiponectin knockout (ko) mice developed significantly larger liver tumours. This was reflected in both greater calculated tumour volume (207 ± 463 mm3, n = 21 vs 30.2 ± 70.2 mm3, n = 22; p = 0.049) and liver: body weight ratio (5.5 ± 1.3%, n= 21 vs 4.5 ± 0.47%, n = 22; p = 0.0008). These tumours displayed distinct histological features with steatosis and eosinophilic inclusions. There were no differences in tumour inflammatory markers. Immunoblotting revealed increased activation of the Akt-mTOR pathway in adiponectin ko tumour compared to wild type. Treatment of primary cultured HCC cells with mTOR inhibitors revealed that adiponectin ko tumour cells required higher doses of all inhibitors to reduce proliferation. Primary cultured adiponectin ko HCC cells formed larger tumour spheres and larger subcutaneous tumours at 28 days post-injection into wild type mice, suggesting a more aggressive phenotype (121 ± 157 mm3, n = 12 vs 35.0 ± 35.5 mm3, n = 12; p = 0.043).

Conclusion This study demonstrates that adiponectin loss is associated with larger and more aggressive liver tumours with distinct histological and signalling changes. These tumours display up-regulation of the AktmTOR pathway, which has been shown to be associated with a poor prognosis in human HCC. We propose that obesity and the associated reduced adiponectin may cause a more aggressive tumour phenotype in human HCC.

Item ID:	86254
Item Type:	Article (Abstract)
ISSN:	1440-1746
Copyright Information:	© 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
Date Deposited:	22 Jul 2025 00:20
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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