Abstract IA16: The ceRNA hypothesis and the non-coding revolution in cancer research and therapy

Abstract

Abstract The central dogma of molecular biology, as proposed by Francis Crick, demonstrates that genetic information is transferred from DNA in our genomes to the generation of functional proteins, through a messenger RNA (mRNA) intermediate. This suggests that the key function of each mRNA is to encode for protein. We have demonstrated that mRNAs can exert a biological activity that is independent of the protein for which they encode. Since this phenomenon is dependent on sequences contained in RNA transcripts, this phenomenon applies to protein-coding genes, pseudogenes, of which 19,000 have been predicted in the genome as well as long non-coding RNAs that have been recently identified to be pervasive in the cell and in biology. This new function is brought about by the ability of mRNAs—and RNAs in general—to bind and sequester microRNA molecules. microRNAs specifically repress the expression levels of many genes and have consequently been shown to play important roles in diseases including cancer. We show that any messenger RNA and RNA molecule can sequester microRNA molecules acting as a “competitive endogenous RNAs.” We therefore term them ceRNAs. Given that microRNAs can bind to multiple mRNAs, we argued that mRNAs compete for the binding to a given microRNA. We originally tested this hypothesis and proved its validity by studying the interaction between the mRNA encoding for the PTEN tumor suppressor gene and its closely related pseudogene, PTENP1, which we show to act as a tumor suppressor through this new mechanism. We therefore identify PTENP1 as well as the several thousand uncharacterized RNA molecules as potential human disease genes. We have now expanded this analysis to the whole transcriptome. Our findings therefore defines a new biological dimension that will allow for the rapid identification and functional characterization of new disease genes. Citation Format: Pier Paolo Pandolfi. The ceRNA hypothesis and the non-coding revolution in cancer research and therapy [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr IA16.