<div>Abstract<p>Loss or attenuated expression of the tumor-suppressor gene <i>FHIT</i> is associated paradoxically with poor progression of human tumors. Fhit promotes apoptosis and regulates reactive oxygen species; however, the mechanism by which Fhit inhibits tumor growth in animals remains unclear. In this study, we used a multidisciplinary approach based on bioinformatics, small RNA library screening, human tissue analysis, and a xenograft mouse model to identify a novel member of the miR-548 family in the fourth intron of the human <i>FHIT</i> gene. Characterization of this human-specific microRNA illustrates the importance of this class of microRNAs in tumor suppression and may influence interpretation of Fhit action in human cancer. <i>Cancer Res; 74(8); 2283–94. ©2014 AACR</i>.</p></div>