The central dogma of gene expression is that DNA is transcribed into messenger RNAs, which in turn serve as the template for protein synthesis. Recently, it has been reported that mRNAs display regulatory roles that rely on their ability to compete for microRNA binding, independent of their protein-coding function. However, the regulatory mechanism of mRNAs remains poorly understood. Here, we report that a hairpin within YAP mRNA 3 ' untranslated region (3 ' UTR) functions in regulation at post-transcription level through generating endogenous siRNAs (esiRNAs). Bioinformatics analysis for secondary structure showed that YAP mRNA displayed a hairpin structure (termed standard hairpin, S-hairpin) within its 3 ' UTR. Surprisingly, we observed that the overexpression of S-hairpin derived from YAP 3 ' UTR (YAP-sh) increased the luciferase reporter activities of transcriptional factor NF-kappa B and AP-1 in 293T cells. Moreover, we identified that a fragment from YAP-sh, an esiRNA, was able to target mRNA 3 ' UTR of NF2 (a member of Hippo-signaling pathway) and YAP mRNA 3'UTR itself in hepatoma cells. Thus, we conclude that the YAP-sh within YAP mRNA 3 ' UTR may serve as a novel regulatory element, which functions in regulation at post-transcription level. Our finding provides new insights into the mechanism of mRNAs in regulatory function. (C) 2015 Elsevier Inc. All rights reserved.