Downregulation of pathways implicated in liver inflammation and tumorigenesis of glycogen storage disease type Ia mice receiving gene therapy

• Published in: Human molecular genetics 2017-05, Vol.26 (10), p.1890-1899
• Main Authors: Kim, Goo-Young, Kwon, Joon Hyun, Cho, Jun-Ho, Zhang, Lisa, Mansfield, Brian C, Chou, Janice Y
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; beta Catenin - genetics; Cadherins - genetics; Carcinogenesis - metabolism; Disease Models, Animal; Down-Regulation; Gene Expression; Genetic Therapy; Genetic Vectors; Glucose-6-Phosphatase - genetics; Glucose-6-Phosphatase - metabolism; Glycogen Storage Disease Type I - therapy; Inflammation - metabolism; Liver - metabolism; Liver Neoplasms - metabolism; Mice; NF-kappa B; Signal Transduction; Sirtuin 1 - metabolism; STAT3 Transcription Factor
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddx097

Glycogen storage disease type Ia (GSD-Ia) is characterized by impaired glucose homeostasis and long-term risks of hepatocellular adenoma (HCA) and carcinoma (HCC). We have shown that the non-tumor-bearing (NT), recombinant adeno-associated virus (rAAV) vector-treated GSD-Ia mice (AAV-NT mice) expressing a wide range (0.9-63%) of normal hepatic glucose-6-phosphatase-α activity maintain glucose homeostasis and display physiologic features mimicking animals living under calorie restriction (CR). We now show that in AAV-NT mice, the signaling pathways of the CR mediators, AMP-activated protein kinase (AMPK) and sirtuin-1 are activated. AMPK/sirtuin-1 inhibit the activity of STAT3 (signal transducer and activator of transcription 3) and NFκB (nuclear factor κB), the pro-inflammatory and cancer-promoting transcription factors. Sirtuin-1 also inhibits cancer metastasis via increasing the expression of E-cadherin, a tumor suppressor, and decreasing the expression of mesenchymal markers. Consistently, in AAV-NT mice, hepatic levels of active STAT3 and NFκB-p65 were reduced as were expression of mesenchymal markers, STAT3 targets, NFκB targets and β-catenin targets, all of which were consistent with the promotion of tumorigenesis. AAV-NT mice also expressed increased levels of E-cadherin and fibroblast growth factor 21 (FGF21), targets of sirtuin-1, and β-klotho, which can acts as a tumor suppressor. Importantly, treating AAV-NT mice with a sirtuin-1 inhibitor markedly reversed many of the observed anti-inflammatory/anti-tumorigenic signaling pathways. In summary, activation of hepatic AMPK/sirtuin-1 and FGF21/β-klotho signaling pathways combined with down-regulation of STAT3/NFκB-mediated inflammatory and tumorigenic signaling pathways can explain the absence of hepatic tumors in AAV-NT mice.