3103

Purpose/Objectives:

MicroRNAs (miRNAs) are novel global regulatory RNAs originally discovered in C. elegans and found to play a significant role as human cancer loci. MiRNAs are aberrantly expressed in tumors compared to normal tissues and regulate proteins known to be critical for pro-survival pathways. These findings indicate that miRNA misregulation likely plays a role in tumor cell transformation. We hypothesized that miRNAs might play a role in a cancer cell's response to cytotoxic therapy and therefore might be a potential target to impact the radiation response.

Materials/Methods:

We have developed a tissue-model of radiation-induced reproductive cell death in the nematode C. elegans, called Radelegans. Reproductive cell death is the primary mode of death in tissue clonogens, the targets of cytotoxic therapy, responsible for solid tumor eradication. We began by evaluating the impact of the miRNA let-7 on the radiosensitivity phenotype in this system. To validate the significance of let-7 on the radiation response we performed miRNA microarrays post-irradiation as well as evaluated the effect of altering expression levels of let-7 in a well-established cell culture system.

Results:

We have found that the miRNA, let-7, significantly impacts the radiation response in Radelegans, with its loss leading to radioresistance and its overexpression leading to radiosensitivity. This is likely due to its regulation of the RAS oncogene as well as numerous additional downstream targets. We further have found that in mammalian cells all but one of the let-7 homologues is immediately downregulated in response to radiation, implicating this family of miRNAs in the cell's response to radiation. In addition, using a tissue-culture system we have found that altering the levels of let-7 in mammalian cells is a means to alter the radiation response. These findings will be further validated in mouse models.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA