Mutual Suppression of MiR-125a and Lin28b in Human Hepatocellular Carcinoma Cells

MicroRNA-125a exhibits an antiproliferative activity and is downregulated in several types of tumors, including hepatocellular carcinoma where it targets sirtuin-7, matrix metalloproteinase-11, and c-Raf. Another target of miR-125a is Lin28, a pluripotency factor that is generally undetectable in differentiated cells but is often upregulated/reactivated in tumors where it acts as an oncogenic factor promoting cell proliferation and tumor progression. In this study we show that downregulation of Lin28b by miR-125a partially accounts for its antiproliferative activity toward hepatocellular carcinoma cells. We also found that Lin28b is able to bind a conserved GGAG motif of pre-miR-125a and to inhibit its maturation in hepatocellular carcinoma cells. Reciprocal inhibition between miR-125a and Lin28b reasonably generates a positive feedback loop where reactivation of Lin-28b inhibits the expression of both miR-125a and let-7, reinforcing its own expression and leading to a marked overexpression of the mitogenic targets of the two miRNAs. On the other hand, perturbation of these circuits by overexpression of miR-125a suppresses Lin28b leading to a decreased cell proliferation. Overall, these data support a tumor suppressive role for miR-125a and contribute to the elucidation of its molecular targets.