Abstract 977: 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. We are studying the role of miR-155 in promoting hypoxia-driven tumor phenotypes such as therapy resistance and genomic instability. Previously, we have shown 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. Additionally, we have shown that by knocking down expression of miR-155 under hypoxic conditions, we were able to sensitize these cells to ionizing radiation. Here, we demonstrate that miR-155 expression is tightly linked to genomic instability, another characteristic of hypoxia. We have found that over-expression of miR-155 drives increased mutation frequency as measured by a mutation reporter assay screen both in vitro and in vivo. These results are consistent with a recent finding that miR-155 over-expression targets mismatch repair proteins, MLH1, MSH2, and MSH6. An increase in mutation frequency could be due to a decrease in mismatch repair function. Surprisingly, we have also found that loss of miR-155 increases the baseline level of double strand breaks observed in a fibroblast cell line. 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. Citation Format: Jennifer Czochor, Peter M. Glazer. Characterizing the regulation and function of miR-155 in hypoxia biology. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 977. doi:10.1158/1538-7445.AM2014-977