Highly upregulated in liver cancer (HULC), a lncRNA that is considered a key molecule in human liver cancer, has recently been revealed to be involved in hepatocellular carcinoma (HCC) development and progression [1, 2]. It has been reported that HULC can promote tumor invasion and metastasis of HCC, but its function and mechanism of action in HCC have not been elucidated. In this study, we found that HULC was aberrantly up-regulated in HCC tissues and associated with TNM stage, intrahepatic metastases, HCC recurrence, and postoperative survival. HULC depletion inhibited the growth and metastasis of HCC cell lines in vitro and in vivo. Moreover, HULC contributes to ZEB1-induced epithelial-mesenchymal transition (EMT), a requirement for tumor invasion and metastasis that plays a key role in cancer progression. This effect of ZEB1 was inhibited by HULC siRNA. We conclude that the HULC functioned as a competing endogenous RNA (ceRNA) to mediate EMT via up-regulating ZEB1. In this way, it sequesters the miR-200a-3p signaling pathway to facilitate HCC metastasis. HULC comes into play as an oncogene in HCC, acting mechanistically by inducing HCC cells to activate EMT. Such an effect promotes tumor progression and metastasis through the miR-200a-3p/ZEB1 signaling pathway. The identification of this novel pathway that links high expression levels of HULC with EMT in HCC cells may serve as the foundation for the development of novel anti-tumor therapeutics.

To study the mechanism of interleukin-6 (IL-6) induction of human C-reactive protein (CRP) gene expression, we have utilized a human hepatoma (PLC/PRF/5) cell culture system to analyze the trans-acting factors which bind to the 300 bp 5'-flanking region of human CRP gene. In vitro gel mobility shift analyses and methylation interference assays demonstrated that NFIL-6 alpha interacted with two IL-6 responsive elements, and HNF-1 alpha and HNF-3/Octamer-like factors interacted with the downstream IL-6 responsive element in the human CRP promoter. In vivo functional analysis by transient transfection of plasmid constructs containing site-specific mutations in one or two IL-6 responsive elements in the CRP promoter fused to a reporter gene, chloramphenicol acetyl transferase (CAT), demonstrated that the binding of NFIL-6 alpha to two IL-6 responsive elements resulted in synergistic induction of the gene. When HNF-1 alpha or HNF-3/Octamer-like factors were independently bound to their corresponding sites, they had either a positive or negative effect, respectively, on IL-6 inducible transcriptional activity.

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