The role of competitive endogenous RNA in cancer

The central hypothesis of this proposal is that deregulation of cancer-associated genes by protein-coding and non- protein-coding RNAs promotes tumor development. miRNAs, negative regulators of translation, are now recognized as modulators of multiple cell biological processes including oncogenesis. Recently, pseudogenes were described to compete for miRNA binding with their cognate protein-coding genes, thereby regulating miRNA availability. This process, termed sponging, relies on the high homology of the respective 3`UTRs and may not only attribute a biological function to pseudogenes but also represent a novel mechanism of gene regulation. Protein coding and non-protein coding RNAs are likely to fine-tune gene expression through sponging and perturbation of this process may promote the development of cancer. Here, I propose an ambitious, yet focused and feasible approach to investigate the contribution of aberrant endogenous sponging to the formation of melanoma. The sponging-mediated regulation of the tumor suppressor PTEN and the proto-oncogene BRAF, two genes commonly associated with melanomagenesis, will be analyzed. Specifically, several protein-coding mRNAs will be probed for their ability to act as `coding sponges` for PTEN and the melanoma-promoting effect of their deregulation will be defined. Furthermore, a transgenic mouse model harboring a Tet-inducible BRAF pseudogene (BRAFps) allele will be generated and utilized to characterize the functional relationship between BRAF and BRAFps and its contribution to melanoma formation determined. The proposed study will provide further insight into the functional relationship of gene-pseudogene pairs and establish sponging as a global gene regulatory process, that, when deregulated, may contribute to cancer development. This work will warrant further research into sponging in physiological and pathological conditions and such knowledge will be useful to devise alternative therapeutic approaches to target cancer.

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