Abstract CN07-04: RNAi in the treatment and epigenetics of cancer

RNA interference is a broad term used to describe several different mechanisms for regulation of gene expression mediated by small RNAs. Small interfering RNAs (siRNAs) trigger sequence specific cleavage of mRNAs via fully complementary base pairing, resulting in cleavage and subsequent total degradation of the targeted transcript. Micro RNAs (miRNAs) are the guides for triggering translational inhibition of gene expression via partially complementary pairing to the 3′ UTRs of target transcripts. Small RNAs can also modulate gene expression via directing chromatin remodeling, resulting in heterochromatin formation and silencing of transcription. Each of these mechanisms has important implications for the prevention and diagnosis of cancer. SiRNAs are not commonly found in mammalian cells, but may be present during gametogenesis to control retroposon movement. The functional consequences of aberrations in the production and functioning of siRNAs could lead to genomic rearrangements and other chromosome abnormalities. MiRNAs have been shown to be important micro‐managers of gene expression, and a single miRNA can repress translation of upwards of two hundred different proteins. MiRNA profiling has shown that aberrant expression of these micro‐managers can be diagnostic and prognostic for several different cancers. Given the importance of miRNAs in controlling cell fates and ultimately progression to cancer, it is important to understand what types of aberrations can affect their function. Micro RNAs are produced via a two step processing reaction involving two different RNAse III family members (Drosha and Dicer) and their cofactors. Perturbations of either of these processing steps can alter the amount and even the final processed sequence of miRNAs. The first part of this presentation will focus on naturally occurring point mutations identified in X‐linked miRNA genes and the consequences of these mutations on miRNA function. Point mutations in miRNA precursors as well as mature sequences can lead to altered miRNA function and could have a profound effect on regulation of the translation of both targeted and non‐targeted mRNAs.

Small RNAs that can modulate chromatin structure also present a possible tool for cancer prevention. Two examples of small RNAs modulating chromatin structure will be presented. The first example is the use of promoter targeting siRNAs to silence an important tumor suppressor, RASFF1A. The second example illustrates how an endogenous microRNA targeting a promoter region can modulate expression of an essential RNA Polymerase 3 subunit.

The last part of this presentation will focus on some strategies for delivering siRNAs or miRNAs in a targeted fashion to modulate expression of genes. These strategies could be useful in cancer prevention and as cancer treatments.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):CN07-04.