Active glycolytic metabolism in CD133(+) hepatocellular cancer stem cells: regulation by MIR-122

Although altered metabolic pathway is an important diagnostic maker and therapeutic target in cancer, it is poorly understood in cancer stem cells (CSCs). Here we show that the CD133 (+) hepatocellular CSCs have distinct metabolic properties, characterized by more active glycolysis over oxidative ph...

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Bibliographic Details
Published in:Oncotarget 2015-12, Vol.6 (38), p.40822-40835
Main Authors: Song, Kyoungsub, Kwon, Hyunjoo, Han, Chang, Zhang, Jinqiang, Dash, Srikanta, Lim, Kyu, Wu, Tong
Format: Article
Language:English
Subjects:
AC133 Antigen
Adenosine Triphosphate - metabolism
Antigens, CD - metabolism
Blotting, Western
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
Cell Proliferation
Gene Expression Regulation, Neoplastic
Glycolysis - physiology
Glycoproteins - metabolism
Humans
Immunoenzyme Techniques
Lactic Acid - metabolism
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
MicroRNAs - genetics
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
Peptides - metabolism
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Real-Time Polymerase Chain Reaction
Research Paper
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - genetics
Spheroids, Cellular - metabolism
Spheroids, Cellular - pathology
Tumor Cells, Cultured
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Summary:Although altered metabolic pathway is an important diagnostic maker and therapeutic target in cancer, it is poorly understood in cancer stem cells (CSCs). Here we show that the CD133 (+) hepatocellular CSCs have distinct metabolic properties, characterized by more active glycolysis over oxidative phosphorylation, compared to the CD133 (-) cells. Inhibition of PDK4 and LDHA markedly suppresses CD133 (+) stemness characteristics and overcome resistance to sorafenib (current chemotherapeutic agent for hepatocellular cancer). Addition of glucose or lactate to CD133 (-) cells promotes CSC phenotypes, as evidenced by increased CD133 (+) cell population, elevated stemness gene expression and enhanced spheroid formation. Furthermore, the liver-specific miRNA, miR-122, inhibits CSC phenotypes by regulating glycolysis through targeting PDK4. Our findings suggest that enhanced glycolysis is associated with CD133 (+) stem-like characteristics and that metabolic reprogramming through miR-122 or PDK4 may represent a novel therapeutic approach for the treatment of hepatocellular cancer.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.5812