Induction of autophagy and apoptosis by miR-148a through the sonic hedgehog signaling pathway in hepatic stellate cells.

Xu-You Liu, Ya-Jun He, Qi-Hong Yang, Wei Huang, Zhi-He Liu, Guo-Rong Ye, Shao-Hui Tang, Jian-Chang Shu

Autophagy is an evolutionarily conserved biological process that is activated in response to stress. Increasing evidence indicate that dysregulated miRNAs significantly contribute to autophagy and are thus implicated in various pathological conditions, including hepatic fibrosis. MiR-148a, a member of the miR-148/152 family, has been found to be downregulated in hepatic fibrosis and human hepatocellular carcinoma. However, the role of miR-148a in the development of hepatic fibrosis remains largely unknown. In this study, we describe the epigenetic regulation of miR-148a and its impact on autophagy in hepatic stellate cells (HSCs), exploring new targets of miR-148a. We found that miR-148a expression was significantly increased under starvation-induced conditions in LX-2 and T-6 cells. In addition, dual-luciferase reporter assays showed that miR-148a suppressed target gene expression by directly interacting with the 3'-untranslated regions (3'-UTRs) of growth arrest-specific gene 1 (Gas1) transcripts. Intriguingly, Gas1, which encodes a Hedgehog surface binding receptor and facilitates the Hedgehog (Hh) signaling pathway, inhibited autophagosome synthesis. Furthermore, we demonstrated a novel function for miR-148a as a potent inducer of autophagy in HSCs. Overexpressing of miR-148a increased autophagic activity, which inhibited proliferation and promoted apoptosis in HSCs. In conclusion, these data support a novel role for miR-148a as a key regulator of autophagy through the Hh signaling pathway, making miR-148a a potential candidate for the development of novel therapeutic strategies.