Here, we report how miRNAs regulate PCAT-1 expression and also investigate the biological significance of this regulation in hepatocellular carcinoma (HCC). We found that miR-215, a P53-inducible miRNA, is a key regulator of PCAT-1 expression in HCC and identified an interaction between miR-215 and PCAT-1 in dual luciferase reporter gene assays. We also found that posttranscriptional silencing of PCAT-1 by miR-215 or PCAT-1 siRNAs significantly inhibited proliferation of HCC cells and, conversely, that inhibition of endogenous miR-215 upregulated PCAT-1 expression and promoted cell viability. The tumor-suppressing role of miR-215 was further confirmed in an in vivo mouse HCC xenograft model. Of note, gene profiling assays suggested that the kinase CRKlike proto-oncogene, adaptor protein (CRKL) is a potential downstream target of the miR-215- PCAT-1 axis in HCC, and we demonstrated that CRKL silencing significantly suppresses cell proliferation.