Back to Search
Start Over
Activation of tumor-promoting pathways implicated in hepatocellular adenoma/carcinoma, a long-term complication of glycogen storage disease type Ia
- Source :
- Biochem Biophys Res Commun
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
G6PC
Carcinoma, Hepatocellular
Carcinogenesis
NF-E2-Related Factor 2
Biophysics
mTORC1
Glycogen Storage Disease Type I
Mechanistic Target of Rapamycin Complex 1
PKM2
Biochemistry
Article
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Autophagy
medicine
Animals
Glycolysis
Molecular Biology
Glycogen
Chemistry
Liver Neoplasms
Cell Biology
Hepatocellular adenoma
medicine.disease
030104 developmental biology
Liver
Anaerobic glycolysis
030220 oncology & carcinogenesis
Glucose-6-Phosphatase
Cancer research
Signal Transduction
Subjects
Details
- ISSN :
- 0006291X
- Volume :
- 522
- Database :
- OpenAIRE
- Journal :
- Biochemical and Biophysical Research Communications
- Accession number :
- edsair.doi.dedup.....654ca9b16e1a6df39ad405fb7dae7a2e