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

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The thyroid hormone, 3,3′,5-triiodo-L-thyronine (T3), regulates cell growth, development and differentiation via interactions with thyroid hormone receptors (TR), but the mechanisms underlying T3-mediated modulation of cancer progression are currently unclear. Lipocalin 2 (LCN2), a tumor-associated protein, is overexpressed in a variety of cancer types. Oligonucleotide microarray, coupled with proteomic analysis, has revealed that LCN2 is positively regulated by T3/TR. However, the physiological role and pathway of T3-mediated regulation of LCN2 in hepatocellular carcinogenesis remain to be characterized. Upregulation of LCN2 after T3 stimulation was observed in a time- and dose-dependent manner. Additionally, TRE on the LCN2 promoter was identified at positions −1444/−1427. Overexpression of LCN2 enhanced tumor cell migration and invasion, and conversely, its knockdown suppressed migration and invasion, both in vitro and in vivo. LCN2-induced migration occurred through activation of the Met/FAK cascade. LCN2 was overexpressed in clinical hepatocellular carcinoma (HCC) patients, compared with normal subjects, and positively correlated with TRα levels. Both TRα and LCN2 showed similar expression patterns in relation to survival rate, tumor grade, tumor stage and vascular invasion. Our findings collectively support a potential role of T3/TR in cancer progression through regulation of LCN2 via the Met/FAK cascade. LCN2 may thus be effectively utilized as a novel marker and therapeutic target in HCC.

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Thyroid hormone, 3,3′,5-triiodo-l-thyronine (T3), mediates several physiological processes, including embryonic development, cellular differentiation and cell proliferation, via binding to its nuclear thyroid receptors (TR). Previous microarray and Chromatin immunoprecipitation (ChIP)-on-ChIP analyses have revealed that interferon-stimulated gene 20 kDa (ISG20), an exoribonuclease involved in the antiviral function of interferon, is up-regulated by T3 in HepG2-TR cells. However, the underlying mechanisms of ISG20 action in tumor progression remain unknown to date. Here, we verified induction of ISG20 mRNA and protein expression by T3 in HepG2-TR cells. Based on the ChIP-on-ChIP database, potential thyroid hormone responsive element of the ISG20 promoter region was predicted, and the result confirmed with the ChIP assay. Functional assays showed that forced expression of ISG20 leads to significant promotion of metastasis and angiogenesis, both in vitro and in vivo. Furthermore, the angiogenic-related protein, interleukin-8 (IL-8), was up-regulated through a T3-mediated increase in ISG20, as determined using a human angiogenesis array kit. Induction of IL-8 signaling activated the p-JAK2/p-STAT3 pathway, in turn, leading to promotion of tumor metastasis and angiogenesis. Furthermore, ISG20 overexpression in hepatocellular carcinoma (HCC) specimens was positively correlated with clinical parameters, including vascular invasion, α-fetoprotein and tumor size. Higher ISG20 expression was significantly correlated with poorer recurrence-free survival in HCC patients. Our results collectively indicate higher TR-dependent expression of ISG20 in a subset of HCC, supporting an oncogenic role in HCC progression.