Dicer mediating the expression of miR-143 and miR-155 regulates hexokinase II associated cellular response to hypoxia.

Lung alveolar epithelial cells are exposed to hypoxia under a variety of physiological and pathological conditions. It has been shown recently that miR-143, which can directly target the key glycolytic enzyme hexokinase II (HK2), may be regulated by miR-155. We investigated whether microRNAs contribute to the cellular glycolysis in response to hypoxia. Using the A549 cells, we found that the expression of Dicer is decreased under hypoxia. When Dicer was knocked down with small-interfering RNA (siRNA), pre-miR143 was increased and mature miR-143 was decreased as that in hypoxia, indicating that reduction of Dicer is responsible for the change of miR-143 under hypoxia. Interestingly, both hypoxia and knockdown of Dicer resulted in miR-155 and pre-miR-155 expression increases. We also examined the expression of HK2 and glucose metabolism in the cells. Both HK2 mRNA and protein were increased under hypoxia, which is accompanied by an increase of glucose uptake and production of lactate. The same alterations were found with siRNA Dicer knockdown. Moreover, transfection with anti-miR-143 also led to a HK2 production and an increase of glucose uptake and lactate production, whereas anti-miR-155 had opposite effects. The miR-143 and anti-miR-155 transfection resulted in a significant cell apoptosis. The expression of Dicer was decreased with HK2 accumulating in mouse lung tissues under hypoxia identified by immunohistochemistry. The changes of miR-143 and miR-155 were similar to those in A549 cells. Our data demonstrate that Dicer regulation of miRNAs promotes HK2 activation and glycolysis, which might protect the cell from hypoxic damage and enter into an adaptive process.