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.

Hepatocellular Carcinoma‐Associated Protein TD26 Interacts and Enhances Sterol Regulatory Element‐Binding Protein 1 Activity to Promote Tumor Cell Proliferation and Growth

“…However, although the treatment of chloroquine, an autophagy inhibitor, apparently blocked the autophagy flux, it had no effect on TD26‐mediated HCC proliferation enhancement (http://onlinelibrary.wiley.com/doi/10.1002/hep.30030/suppinfo), suggesting that autophagy is not related to TD26‐mediated tumor cell proliferation. Because abnormal glucose and lipid metabolism have been suggested to be involved in HCC development, we started to examine whether TD26 can affect glucose or lipid metabolism in HCC cells. Consistent with previous findings showing that TD26 has no effect on glucose metabolism, our MS assays also demonstrated that neither TD26 overexpression nor knockdown changes the glucometabolic profiles in HCC cells (http://onlinelibrary.wiley.com/doi/10.1002/hep.30030/suppinfo).…”

“…S3B,C), suggesting that autophagy is not related to TD26-mediated tumor cell proliferation. Because abnormal glucose and lipid metabolism have been suggested to be involved in HCC development, (11,31,32) we started to examine whether TD26 can affect glucose or lipid metabolism in HCC cells. Consistent with previous findings showing that TD26 has no effect on glucose metabolism, (17) our MS assays also demonstrated that neither TD26 overexpression nor knockdown changes the glucometabolic profiles in HCC cells (Supporting Fig.…”

Lipocalin 2 negatively regulates cell proliferation and epithelial to mesenchymal transition through changing metabolic gene expression in colorectal cancer

“…However, we observed that LCN2 silencing induced cell proliferation accompanied by high glycolysis. Accelerated glycolysis meets the demands of rapid cell proliferation and offers a favorable microenvironment for tumor progression . Moreover, among the glucose translocation carriers, GLUT1 expression has been correlated with malignant features and poor prognosis in various cancers, including prostate, thyroid, CRC, liver and breast cancer .…”

“…Accelerated glycolysis meets the demands of rapid cell proliferation and offers a favorable microenvironment for tumor progression. (30) Moreover, among the glucose translocation carriers, GLUT1 expression has been correlated with malignant features and poor prognosis in various cancers, including prostate, thyroid, CRC, liver and breast cancer. (31)(32)(33)(34)(35) Therefore, this study provides clear evidence that LCN2 negatively modulated CRC cell proliferation with reprogramming of energy metabolism, based on glucose consumption, lactate production and the expression level of key enzymes in glucose metabolism.…”

Glycine N-methyltransferase deletion in mice diverts carbon flux from gluconeogenesis to pathways that utilize excess methionine cycle intermediates

“…This atypical metabolic phenotype is thought to provide energetic support for the biosynthetic demand of tumorigenesis (12). Indeed, HCC often displays an accelerated rate of glycolytic flux (13). However, the liver is unique, given it has a high capacity for both glucose utilization and formation.…”