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 0 untranslated region of adenosine monophosphate-activated protein kinase subunit beta 2 (AMPKb2).The TUG1/miR-455-3p/AMPKb2 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, AMPKb2, 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) H epatocellular carcinoma (HCC) is one of the most common malignant liver tumors worldwide. Long-term prognosis for HCC remains extremely poor, with metastasis being the major underlying cause of mortality.(1) Advances in our understanding of the mechanisms underlying metastasis in HCC and strategies to enhance the efficacy of current treatment options are essential to improve prognosis.The metabolic properties of cancer cells are distinct from those of normal cells.(2) Cancer cells exhibit unique metabolic phenotypes, such as enhanced uptake of glucose and conversion of pyruvate to lactate. This phenomenon, termed the Warburg effect, confers Abbreviations: 2-DG, 2-deoxyglucose; AMPKb2, adenosine monophosphate-activated protein kinase subunit beta 2; ChIP, chromatin immunoprecipitation; EED, embryonic ectoderm development; EZH2, enhancer of zeste homolog

No abstract

Thyroid hormone (T 3 ) mediates cellular growth, development, and differentiation by binding to the nuclear thyroid hormone receptor (TR). Recent studies suggest that long-term hypothyroidism is associated with human hepatocellular carcinoma (HCC) independent from other major HCC risk factors. Dickkopf (DKK) 4, a secreted protein, antagonizes the Wnt signal pathway. In this study, we demonstrate that T 3 may play a suppressor role by inducing DKK4 expression in HCC cells at both the messenger RNA (mRNA) and protein levels. DKK4 was down-regulated in 67.5% of HCC cancerous tissues. The decrease in DKK4 levels was accompanied by a concomitant decrease in TR protein levels in the matched cancerous tissues in 31% of tissues compared by immunoblotting with the adjacent noncancerous tissues. Further, TR and DKK4 expression levels were positively correlated in both normal and cancerous specimens by tissue array analysis. In function assays, stable DKK4 transfected into J7 or HepG2 cells decreased cell invasion in vitro. Conversely, knocking down DKK4 restores cell invasiveness. DKK4-expressing J7 clones showed increased degradation of b-catenin, but down-regulation of CD44, cyclin D1, and c-Jun. To investigate the effect of DKK4 and TR on tumor growth in vivo, we established a xenograft of J7 cells in nude mice. J7-DKK4 and J7-TRa1 overexpressing mice, which displayed growth arrest, lower lung colony formation index, and smaller tumor size than in control mice, supporting an inhibitory role of DKK4 in tumor progression. Conclusion: Taken together, these data suggest that the TR/DKK4/Wnt/b-catenin cascade influences the proliferation and migration of hepatoma cells during the metastasis process and support a tumor suppressor role of the TR. (HEPATOLOGY 2012;55:910-920) T hyroid hormone, 3,3 0 -5-triiodo-l-thyronine (T 3 ), is a potent mediator of many physiological processes including embryonic development, cell differentiation, metabolism, and the regulation of cell proliferation.1,2 The actions of T 3 are mediated by nuclear thyroid hormone receptors (TRs). TRs are ligand-dependent transcription factors that comprise modular functional domains that mediate hormone binding (ligands), DNA binding, receptor homo-and heterodimerization, and interaction with other transcription factors and cofactors.3 TRs are derived from two genes, TRa and TRb, located on human chromosomes 17 and 3, respectively. Transcripts of each of these genes undergo alternative promoter choice to generate TRa1 and TRa2 as well as TRb1 and TRb2 receptor isoforms. 2-4Using a complementary DNA (cDNA) microarray technique, we previously identified 148 genes that are positively regulated by T 3 in a TRa1-overexpressing

The imbalanced regulation of metabolic homeostasis and energy production is highly associated with inflammation, tumor growth, metastasis and cancer progression. Both glycolysis and oxidative phosphorylation maintain metabolic homeostasis and energy production in cells. Long noncoding RNAs (lncRNAs) are a class of non-protein-coding transcripts longer than 200 nucleotides. Furthermore, lncRNAs can function as either tumor suppressors or oncogenes in cancer. Dysregulated lncRNAs reportedly regulate cancer hallmarks such as tumor growth, metabolism and metastasis. Accordingly, uncovering the interaction between lncRNAs and cellular metabolism has become a necessity when attempting to identify effective therapeutic and preventive strategies in cancer progression. This review summarizes important knowledge of the actions of known lncRNAs-mediated cancer metabolism.