Activation of tumor-promoting pathways implicated in hepatocellular adenoma/carcinoma, a long-term complication of glycogen storage disease type Ia

• Published in: Biochemical and biophysical research communications 2020-01, Vol.522 (1), p.1-7
• Main Authors: Cho, Jun-Ho, Lee, Young Mok, Bae, Seong-Ho, Chou, Janice Y.
• Format: Article
• Language: English
• Subjects: Animals; Autophagy; Autophagy impairment; Carcinogenesis - metabolism; Carcinogenesis - pathology; Carcinoma, Hepatocellular - etiology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Glucose-6-Phosphatase - metabolism; Glycogen Storage Disease Type I - complications; Glycogen Storage Disease Type I - metabolism; Glycogen Storage Disease Type I - pathology; Liver - metabolism; Liver - pathology; Liver cancer; Liver Neoplasms - etiology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Mechanistic Target of Rapamycin Complex 1 - metabolism; Metabolism; Mice; NF-E2-Related Factor 2 - metabolism; p62 accumulation; Signal Transduction
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.11.061

Hepatocellular adenoma/carcinoma (HCA/HCC) is a long-term complication of the metabolic disorder glycogen storage disease type Ia (GSD-Ia) deficient in glucose-6-phosphatase-α (G6PC or G6Pase-α). We have shown previously that hepatic G6Pase-α deficiency leads to autophagy impairment, mitochondrial dysfunction, enhanced glycolysis, and augmented hexose monophosphate shunt, all of which can contribute to hepatocarcinogenesis. However, the mechanism underlying HCA/HCC development in GSD-Ia remains unclear. We now show that G6Pase-α deficiency-mediated hepatic autophagy impairment leads to sustained accumulation of an autophagy-specific substrate p62 which can activate tumor-promoting pathways including nuclear factor erythroid 2-related factor 2 (Nrf2) and mammalian target of rapamycin complex 1 (mTORC1). Consistently, the HCA/HCC lesions developed in the G6Pase-α-deficient livers display marked accumulation of p62 aggregates and phosphorylated p62 along with activation of Nrf2 and mTORC1 signaling. Furthermore, the HCA/HCC lesions exhibit activation of additional oncogenic pathways, β-catenin and Yes-associated protein (YAP) which is implicated in autophagy impairment. Intriguingly, hepatic levels of glucose-6-phosphate and glycogen which are accumulated in the G6Pase-α-deficient livers were significantly lower in HCC than those in HCA. Conversely, compared to HCA, the HCC lesion display increased expression of many oncogenes and the M2 isoform of pyruvate kinase (PKM2), a glycolytic enzyme critical for aerobic glycolysis and tumorigenesis. Collectively, our data show that hepatic G6Pase-α-deficiency leads to persistent autophagy impairment and activation of multiple tumor-promoting pathways that contribute to HCA/HCC development in GSD-Ia. •Hepatic G6Pase-α deficiency leads to sustained autophagy impairment and p62 accumulation.•HCA/HCC in murine GSD-Ia display marked p62 aggregates and p62 phosphorylation.•Nrf2, mTORC1, β-catenin, and YAP pathways are activated in HCA/HCC in murine GSD-Ia.•HCC and HCA in murine GSD-Ia exhibit differential metabolism and oncogenes expression.