Abstract 199: Noncoding RNAs of the 8q24 locus

The 8q24 locus has been found to be involved in many types of cancers as a consequence of somatic changes associated with chromosome instability including amplification, translocation or deletion or frequent viral integration (HPV). A number of SNPs in Genome Wide Association (GWA) studies have also implicated the 8q24 locus as a region of susceptibility for many types of cancer. The most likely 8q24 candidate target may be the MYC proto-oncogene that is a well characterized transcription factor. However, the assumed correlation between MYC expression and disease is lacking suggesting a connection between 8q24 involvement and disease is much more complicated than simply targeting MYC. While other transcription units also reside within the 8q24 locus (PRNCR1, POU5F1P1, PVT1 and the miRNA cluster miR-1204∼1208), they are remarkable in that no coding potential has been readily associated with any of these genes. Thus, the region has been referred to as the “8q24 Gene Desert”. With the renewed realization that many noncoding RNAs do have a functional role, the location of the miR-1204∼1208 cluster of miRNAs within the PVT1 lincRNA transcriptional unit actually suggests an “Oasis of transcription” that could be the additional or alternative target to MYC. We have now compared expression of transcripts of the miR-1204∼1208 cluster with MYC and PVT1 in multiple cancer cell lines and we have found them to be uniformly up-regulated in expression, particularly in those cell lines with amplified or translocated 8q24. These results confirm a pilot study of microdissected primary prostate tumors that also show correlated high expression in MYC, miR-1204∼1208 and PVT1. To further analyze the functional role of the 8q24 transcripts, we have now introduced mimics or inhibitors of each miRNA and siRNAs corresponding to MYC and PVT1 into prostate or colon cell lines (with and without amplified 8q24). In amplified prostate cell lines, mimics of miR-1204, miR-1206 and miR-1208 appear to be as effective as MYC or PVT1 siRNAs in arresting cell growth and inducing apoptosis. This result is not seen in normal prostate cells. Predictably, inhibitors of the miR-1204, miR-1206 and miR-1208 seem to have no effect or seem to enhance cellular proliferation. In colon cell lines with amplified 8q24, miR-1204, miR-1206, miR-1207 and miR-1208 mimics all appear to be as effective in arresting growth as silencing MYC or PVT1. What is particularly striking is that down-regulation or silencing of PVT1 produces the same effect as over-expression (mimic) of the embedded cluster of miRNAs suggesting opposing actions of miRNAs and host transcript. Experiments to determine whether synergy or promoter competition of the PVT1/miR-1204∼1208 cluster is specifically active in amplified 8q24 will be presented. Nevertheless, we can already assign viable functional roles to transcripts besides MYC that could represent alternative molecular targets within the 8q24 locus for cancer susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 199. doi:1538-7445.AM2012-199