Reprogramming of glucose metabolism in hepatocellular carcinoma: Progress and prospects

Abstract

Hepatocellular carcinoma (HCC) is one of the most lethal cancers, and its rate of incidence is rising annually. Despite the progress in diagnosis and treatment, the overall prognoses of HCC patients remain dismal due to the difficulties in early diagnosis and the high level of tumor invasion, metastasis and recurrence. It is urgent to explore the underlying mechanism of HCC carcinogenesis and progression to find out the specific biomarkers for HCC early diagnosis and the promising target for HCC chemotherapy. Recently, the reprogramming of cancer metabolism has been identified as a hallmark of cancer. The shift from the oxidative phosphorylation metabolic pathway to the glycolysis pathway in HCC meets the demands of rapid cell proliferation and offers a favorable microenvironment for tumor progression. Such metabolic reprogramming could be considered as a critical link between the different HCC genotypes and phenotypes. The regulation of metabolic reprogramming in cancer is complex and may occur via genetic mutations and epigenetic modulations including oncogenes, tumor suppressor genes, signaling pathways, noncoding RNAs, and glycolytic enzymes etc. Understanding the regulatory mechanisms of glycolysis in HCC may enrich our knowledge of hepatocellular carcinogenesis and provide important foundations in the search for novel diagnostic biomarkers and promising therapeutic targets for HCC.

Keywords: Aerobic glycolysis; Glucose metabolism; Hepatocellular carcinoma; Metabolic reprogramming; Noncoding RNAs.

Figure 1

Reprogramming of glucose metabolism in hepatocellular carcinoma. Reprogramming of glucose metabolism-related enzymes and transporting proteins in HCC. The expression of GLUT1, GLUT2, HK2, HKDC1, GAPDH, PKM2, LDHA and MCT4 are up-regulated in HCC glycolysis pathway. GLUT: Glucose transporter; HK: Hexokinase; G6P: Glucose-6-phosphate; GPI1: Glucose-6-phosphate isomerase 1; F6P: Fructose-6-phosphate; PFK: Phosphofructokinase; FBP: Fructose-1,6-bisphosphatase; ALDA: Aldolase A, DHAP: Dihydroxyacetone phosphate; TIM: Triosephosphate isomerase; G3P: Glyceraldehyde-3-phosphate; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; PG: Phosphoglycerate; PGAM: Phosphoglycerate mutase; ENO: Enolase; PEP: Phosphoenolpyruvate; PKM2: Pyruvate kinase isoform M2; PFK: Phosphate fructose kinase; LDHA: Lactate dehydrogenase A; MCT4: Monocarboxylate transporter 4.