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

• Published in: Oncotarget Vol. 6; no. 38; pp. 40822 - 40835
• Main Authors: Song, Kyoungsub, Kwon, Hyunjoo, Han, Chang, Zhang, Jinqiang, Dash, Srikanta, Lim, Kyu, Wu, Tong
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 01-12-2015
• 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; cancer stem cells; miR-122; glycolysis; CD133
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.5812

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.