Mechanisms of Oncogenesis by miR-155

Abstract

Tumors develop when abnormalities in a cell accumulate to promote growth and prevent death. These abnormalities can include mutations or changes in gene expression. One type of factor that can contribute to tumor development is microRNAs (miRNAs), which are small non-coding RNAs that repress expression of target genes. miR-155 is an inflammation-associated miRNA that acts as an oncogene in a number of hematological malignancies. Here, we examine the molecular mechanisms by which miR-155 can promote tumor development and progression. We used an inducible transgenic mouse model that overexpresses miR-155 and develops hematological malignancy to understand how cooperation between multiple miR-155 targets drives oncogenesis. One category of miR-155 targets includes DNA repair factors, so we performed whole exome sequencing on tumors from our mouse model and identified a single oncogene, c-Kit, which frequently (>93%) bore activating mutations. Tumor growth was dependent on this c-Kit activity, as treatment with an inhibitor resulted in rapid tumor regression. However, the mutation is not sufficient for tumor growth when miR-155 is not overexpressed, because deactivating the miR-155 transgene also results in tumor regression. We showed that c-Kit expression is dependent on miR-155 expression, indicating that targets of miR-155 that affect c-Kit expression must cooperate miR-155-driven DNA repair deficiency in order for tumors to form and progress. Preliminary data from further studies suggest that this mechanism of oncogenesis is available only under certain conditions. For instance, c-Kit may be epigenetically silenced in adult mice, preventing regulation of its expression by miR-155. This mechanism is also not available when selection pressure is applied by extended treatment with small molecule inhibitors, and under these conditions, other mechanisms seem to be available for miR-155 to promote oncogenesis. Future research could focus on identifying and understanding these additional mechanisms and the contexts in which they are utilized. We present here a new model for multi-step oncogenesis by a miRNA, in which multiple targets cooperate to drive oncogenesis. This model may be applicable to other miRNAs and could inform the use of miRNAs as biomarkers and therapeutics.