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MicroRNAs as Potential Agents to Alter Resistance to Cytotoxic Anticancer Therapy

¹ Department of Therapeutic Radiology, Yale University School of Medicine; and ² Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut

Requests for reprints: Joanne B. Weidhaas, Department of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar Street, P. O. Box 208040, New Haven, CT 06520. Phone: 203-737-4267; Fax: 203-785-6309; E-mail: joanne.weidhaas{at}yale.edu or Frank J. Slack, Department of Molecular, Cellular and Developmental Biology, Yale University, P.O. Box 208103, New Haven, CT 06520. E-mail: frank.slack{at}yale.edu.

Tumor cells use preexisting prosurvival signaling pathways to evade the damaging and cytotoxic effects of anticancer agents. Radiation therapy is a primary form of cytotoxic anticancer treatment, but agents that successfully modify the radiation response in vivo are lacking. MicroRNAs (miRNA) are global gene regulators that play critical roles in oncogenesis and have been found to regulate prosurvival pathways. However, there is little understanding of how cellular miRNA expression affects the response of a cancer to cytotoxic therapy and ultimately outcome. The let-7 family of miRNAs regulates expression of oncogenes, such as RAS, and is specifically down-regulated in many cancer subtypes. In fact, low levels of let-7 predict a poor outcome in lung cancer. Here, we report that the let-7 family of miRNAs is overrepresented in a class of miRNAs exhibiting altered expression in response to radiation. More strikingly, we also can create a radiosensitive state when the select let-7 family of miRNAs is overexpressed in vitro in lung cancer cells and in vivo in a Caenorhabditis elegans model of radiation-induced cell death, whereas decreasing their levels causes radioresistance. In C. elegans, we show that this is partly through control of the proto-oncogene homologue let-60/RAS and genes in the DNA damage response pathway. These findings are the first direct evidence that miRNAs can suppress resistance to anticancer cytotoxic therapy, a common feature of cancer cells, and suggest that miRNAs may be a viable tool to augment current cancer therapies. [Cancer Res 2007;67(23):11111–6]

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