Yang-Hsiang Lin1, Meng-Han Wu1, Ya-Hui Huang2, Chau-Ting Yeh2, Mei-Ling Cheng3,4,5, Hsiang-Cheng Chi1,6, Chung-Ying Tsai1, I-Hsiao Chung1, Ching-Ying Chen1, Kwang-Huei Lin1,2,7. 1. Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan. 2. Department of Biochemistry, College of Medicine, Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 3. Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan. 4. Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan. 5. Clinical Phenome Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 6. Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Taoyuan, Taiwan. 7. Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
Abstract
Cancer cells display altered glucose metabolism characterized by a preference for aerobic glycolysis. The aerobic glycolytic phenotype of hepatocellular carcinoma (HCC) is often correlated with tumor progression and poorer clinical outcomes. However, the issue of whether glycolytic metabolism influences metastasis in HCC remains unclear. In the current study, we showed that knockdown of taurine up-regulated gene 1 (TUG1) induces marked inhibition of cell migration, invasion, and glycolysis through suppression of microRNA (miR)-455-3p. MiR-455-3p, which is transcriptionally repressed by p21, directly targets the 3' untranslated region of adenosine monophosphate-activated protein kinase subunit beta 2 (AMPKβ2). The TUG1/miR-455-3p/AMPKβ2 axis regulates cell growth, metastasis, and glycolysis through regulation of hexokinase 2 (HK2). TUG1 is clearly associated with HK2 overexpression and unfavorable prognosis in HCC patients. CONCLUSION: Our data collectively highlight that novel regulatory associations among TUG1, miR-455-3p, AMPKβ2, and HK2 are an important determinant of glycolytic metabolism and metastasis in HCC cells and support the potential utility of targeting TUG1/HK2 as a therapeutic strategy for HCC. (Hepatology 2018;67:188-203).
Cancer cells display altered glucose metabolism characterized by a preference for aerobic glycolysis. The aerobic glycolytic phenotype of hepatocellular carcinoma (HCC) is often correlated with tumor progression and poorer clinical outcomes. However, the issue of whether glycolytic metabolism influences metastasis in HCC remains unclear. In the current study, we showed that knockdown of taurine up-regulated gene 1 (TUG1) induces marked inhibition of cell migration, invasion, and glycolysis through suppression of microRNA (miR)-455-3p. MiR-455-3p, which is transcriptionally repressed by p21, directly targets the 3' untranslated region of adenosine monophosphate-activated protein kinase subunit beta 2 (AMPKβ2). The TUG1/miR-455-3p/AMPKβ2 axis regulates cell growth, metastasis, and glycolysis through regulation of hexokinase 2 (HK2). TUG1 is clearly associated with HK2 overexpression and unfavorable prognosis in HCC patients. CONCLUSION: Our data collectively highlight that novel regulatory associations among TUG1, miR-455-3p, AMPKβ2, and HK2 are an important determinant of glycolytic metabolism and metastasis in HCC cells and support the potential utility of targeting TUG1/HK2 as a therapeutic strategy for HCC. (Hepatology 2018;67:188-203).