MicroRNA-31 suppresses the self-renewal capability of α2δ1+ liver tumor-initiating cells by targeting ISL1

Accumulating evidence demonstrates that miRNAs, a class of small non-coding RNAs, are involved in the regulation of tumor-initiating cells (TICs) which are considered to be the origin of cancer development according to the cancer stem cell hypothesis. We have previously identified that miR-31 may play suppressive roles in α2δ1+ hepatocellular carcinoma (HCC) TICs. Here, we confirm that the expression of miR-31 is significantly downregulated in α2δ1+ HCC TICs. Overexpression of miR-31 in α2δ1+ HCC TICs results in significant suppression of the self-renewal and tumorigenicity abilities of these cells. Conversely, knockdown the expression of miR-31 in PLC/PRF/5 cells is able to reprogram them into TICs with stem cell-like properties. Furthermore, the expression of ISL LIM Homeobox 1(ISL1), a transcription factor involved in recognition of undifferentiated cardiac progenitors, is negatively regulated by miR-31, and the luciferase reporters' activities with the 3'-UTRs of ISL1 are inhibited significantly by miR-31. Collectively, our results suggest that miR-31 can negatively regulate the self-renewal ability of α2δ1+ liver TICs via silencing ISL1.