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Enterovirus 71 is an enterovirus of the family Picornaviridae. The 2C protein of poliovirus, a relative of enterovirus 71, is essential for viral replication. The poliovirus 2C protein is associated with host membrane vesicles, which form viral replication complexes where viral RNA synthesis takes place. We have now identified a host-encoded 2C binding protein called reticulon 3, which we found to be associated with the replication complex through direct interaction with the enterovirus 71-encoded 2C protein. We observed that the N terminus of the 2C protein, which has both RNA-and membrane-binding activity, interacted with reticulon 3. This region of interaction was mapped to its reticulon homology domain, whereas that of 2C was encoded by the 25th amino acid, isoleucine. Reticulon 3 could also interact with the 2C proteins encoded by other enteroviruses, such as poliovirus and coxsackievirus A16, implying that it is a common factor for such viral replication. Reduced production of reticulon 3 by RNA interference markedly reduced the synthesis of enterovirus 71-encoded viral proteins and replicative doublestranded RNA, reducing plaque formation and apoptosis. Furthermore, reintroduction of nondegradable reticulon 3 into these knockdown cells rescued enterovirus 71 infectivity, and viral protein and double-stranded RNA synthesis. Thus, reticulon 3 is an important component of enterovirus 71 replication, through its potential role in modulation of the sequential interactions between enterovirus 71 viral RNA and the replication complex.

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