Triose-phosphate isomerase is a novel target of miR-22 and miR-28, with implications in tumorigenesis.

Abstract

Aerobic glycolysis is the hallmark of many cancer cells that results in a high rate of adenosine triphosphate (ATP) production and, more importantly, biosynthetic intermediates, which are required by the fast-growing tumor cells. The molecular mechanism responsible for the increased glycolytic influx of tumor cells is still not fully understood. In the present study, we have attempted to address the above question by exploring the role of the glycolytic enzyme, triose-phosphate isomerase (TPI), in the cancer cells. The western blot analysis of the 30 human colorectal cancer samples depicted higher post-transcriptional expression of TPI in the tumor tissue relative to the normal tissue. In addition, we identified two novel microRNAs, miR-22 and miR-28, that target the TPI messenger RNA (mRNA) and regulate its expression. miR-22 and the miR-28 showed significant inverse expression status viz-a-viz the expression of the TPI. The specificity of the miR-22/28 regulation of the TPI mRNA was confirmed by various biochemical and mutagenic assays. Moreover, the hypoxia conditions resulted in an increased expression of the TPI protein, with a concomitant decrease in miR-22/28. The physiological significance of the TPI and miR-22/28 interaction for the glycolytic influx was confirmed by the l-lactate production in the HCT-116+/+ cells. Overall, our data demonstrate the novel microRNA mediated post-transcriptional regulation of the TPI glycolytic enzyme, which may be one of the possible reasons for the increased glycolytic capacity of the tumor cells.