Evidence is accumulating that long non‐coding RNAs (lncRNAs) are involved in human tumorigenesis and dysregulated in many cancers, including hepatocellular carcinoma (HCC). Because lncRNAs can regulate essential pathways that contribute to tumor initiation and progression with their tissue specificity, lncRNAs are valuable biomarkers and therapeutic targets. Maternally expressed gene 3 (MEG3) is a lncRNA overexpressed in HCC cells that inhibits HCC progression, however, the mechanism remains largely unknown. Recently, a novel regulatory mechanism has been proposed in which RNAs can cross‐talk with each other via competing for shared microRNAs (miRNAs). The proposed competitive endogenous RNAs could mediate the bioavailability of miRNAs on their targets, thus imposing another level of post‐transcriptional regulation. In the current study, we demonstrated that MEG3 is down‐regulated in HCC tissues. MEG3 over‐expression imposes another level of post‐transcriptional regulation, whereas MEG3 overexpression increase the expression of the miR‐664 target gene, ADH4, through competitive “sponging” miR‐664. In addition, NF‐κB may affect transcription of MEG3 by directly binding to the promoter region. Our data revealed that NF‐κB may affect the transcript of MEG3. MEG3 overexpression inhibited the proliferation of HCC cells, at least in part by affecting miR‐664mediated regulation of ADH4. Together, these results suggest that MEG3 is a suppressor of tumor which acts in part through “sponging” miR‐664. J. Cell. Biochem. 118: 3713–3721, 2017. © 2017 Wiley Periodicals, Inc.