MicroRNA Inhibitors as Anticancer Therapies.

摘要

MicroRNAs are small, noncoding RNAs that post-transcriptionally regulate gene expression. A polycistronic cluster of microRNAs, miR-17-92, is mis-expressed in a wide range of tumors and tumor cell lines. Ectopic expression of this microRNA cluster in cooperation with c-myc promotes development of B cell lymphoma in a mouse model. We hypothesize that inhibition of the microRNAs within this cluster is a therapeutic approach for the treatment of breast cancer. We undertook several strategies to test this using in vitro models: (1) Antisense inhibitors of microRNAs within the cluster exhibit cytotoxicity of carcinoma cells. This is dependent on nucleic acid modification chemistry. Locked nucleic acid modified antisense molecules exhibited the greatest potency, but lead to non-specific toxicity: (2) We mapped the transcriptional start region and the transcriptional regulation of this microRNA cluster. This cluster is regulated by E2F family transcription factors. Interference with transcription is a possible therapeutic strategy. Targeting of the primary transcript is second novel therapeutic approach. We are currently testing these approaches.