The anti-diabetic drug exenatide, a glucagon-like peptide-1 receptor agonist, counteracts hepatocarcinogenesis through cAMP-PKA-EGFR-STAT3 axis

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Author(s)

  • M. Zhou
  • M. T.S. Mok
  • H. Sun
  • A. W. Chan
  • A. S.L. Cheng
  • G. Xu

Detail(s)

Original languageEnglish
Pages (from-to)4135-4149
Journal / PublicationOncogene
Volume36
Issue number29
Publication statusPublished - 20 Jul 2017
Externally publishedYes

Abstract

Epidemiological studies have demonstrated a close association of type 2 diabetes and hepatocellular carcinoma (HCC). Exenatide (Ex-4), a potent diabetes drug targeting glucagon-like peptide-1 receptor (GLP-1R), is protective against non-alcoholic fatty liver disease (NAFLD). However, the Ex-4 function and GLP-1R status have yet been explored in HCC. Herein we investigated the effect of Ex-4 in diethylnitrosamine (DEN)-treated mice consuming control or high-fat high-carbohydrate diet. Administration of Ex-4 significantly improved obesity-induced hyperglycemia and hyperlipidemia and reduced HCC multiplicity in obese DEN-treated mice, in which suppressed proliferation and induced apoptosis were confined to tumor cells. The tumor suppression effects of Ex-4 were associated with high expression of GLP-1R and activation of cyclic AMP (cAMP) and protein kinase A (PKA). Importantly, Ex-4 also downregulated epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3), which lie downstream of cAMP-PKA signaling, resulting in suppression of multiple STAT3-targeted genes including c-Myc, cyclin D1, survivin, Bcl-2 and Bcl-xl. The growth inhibitory effects of Ex-4 were consistent in GLP-1R-abundant hepatoma cell lines and xenograft mouse model, wherein both PKA and EGFR had obligatory roles in mediating Ex-4 functions. In addition, Ex-4 also effectively suppressed inflammatory and fibrotic phenotypes in mice fed with methionine-choline-deficient (MCD) diet and choline-deficient ethionine-supplemented (CDE) diet, respectively. In summary, Ex-4 elicits protective functions against NAFLD and obesity-associated HCC through cAMP-PKA-EGFR-STAT3 signaling, suggesting its administration as a novel approach to reduce HCC risk in diabetic patients.

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Citation Format(s)

The anti-diabetic drug exenatide, a glucagon-like peptide-1 receptor agonist, counteracts hepatocarcinogenesis through cAMP-PKA-EGFR-STAT3 axis. / Zhou, M.; Mok, M. T.S.; Sun, H.; Chan, A. W.; Huang, Y.; Cheng, A. S.L.; Xu, G.

In: Oncogene, Vol. 36, No. 29, 20.07.2017, p. 4135-4149.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review