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Aberrant activations of Hedegehog (Hh) signaling were found in hepatocellular carcinoma (HCC) and some other cancer types. However, the details have not been completely understood and the underlying mechanism remains unclear. Here we reported that miR-1249 transcription in HCC cells was regulated through direct binding to the conserved sequences in miR-1249 promoter region by Gli1, which functions as a transcription factor and is a component in the Hh signaling pathway. Interestingly, expression of tumor suppressor PTCH1, which is another component of the Hh signaling pathway, was inhibited by miR-1249 through targeting its 3′-untranslated region. Down-regulation of PTCH1 further enhanced the downstream effects mediated by Gli1. In consistent with these findings, miR-1249 expression level was correlated with degree of prognosis (p=0.005) in HCC patients. Taken together, our results suggested the existence of a positive feedback loop comprised of Gli1, miR-1249 and PTCH1. During the process of HCC progression, this positive feedback loop could be continuously activated to enhance tumor cell growth, migration and invasion. [ABSTRACT FROM AUTHOR]