Characterizing the Regulation and Function of miR-155 in Hypoxia Biology

Aberrant expression of microRNAs has been correlated with the initiation and progression of many diseases. One such microRNA, miR-155, is an oncogenic microRNA that has been associated with several different types of cancer, including lung, breast, and lymphoma. Previously, we showed that miR-155 expression is induced under hypoxic conditions and that over-expression of miR-155 under normal oxygen conditions confers resistance to ionizing radiation therapy in lung cancer cells. Additionally, we showed that by knocking down expression of miR-155 under hypoxic conditions, we were able to sensitize these cells to ionizing radiation. Recently, it was suggested that miR-155 over-expression alone was sufficient to induce lymphoma in a conditional miR-155 knock-in mouse model, yet the mechanism behind this phenotype remains unknown. One possible mechanism could be that miR-155
over-expression drives genomic instability. Here, we demonstrate that miR-155 expression level is tightly linked to genomic stability. We have found that over-expression of miR-155 drives increased mutation frequency as measured by a mutation reporter assay screen. An increase in mutation frequency could be due to a decrease in the expression of several mismatch repair proteins, which are known targets of miR-155. Surprisingly, we have also found that loss of miR-155 increases the baseline level of double strand breaks observed
in a fibroblast cell. Taken together, this data suggests that a finite regulation of miR-155 is necessary to maintain cellular homeostasis. Our goal is to gain a better understanding of the role of miR-155 in promoting hypoxic cancer cell survival.