Final Report Summary - CANALU (Unraveling the role of Alu RNAs accumulation in cancer progression) Alu sequences are the most abundant short interspersed repeated elements in the human genome. They are so widely distributed because of their ability to undergo retrotransposition, which has long been considered the main fate of Alu repeats. These DNA elements can be transcribed by RNA polymerase III as ~ 300-nucleotide long. Free Alu transcripts are generally expressed at very low levels, but their abundance increases under various stresses (such as heat shock, hyperglycemia and viral infection) suggesting that these elements could have a role in the regulation of vital cellular processes. Our previous discovery that Alu RNA is degraded by DICER1 and that DICER1 deficiency through accumulation of Alu RNA triggers to macular degeneration, led us to hypothesize that this DICER1/Alu RNA axis could be involved in other human pathologies. In this scenario, the main objective of the present project was to determine the potential role of Alu sequences in cancer pathogenesis, not identified to date. Most of the objectives regarding the scientific project supported by the CIG grant were reached and we published an original manuscript in an international peer review journal, where we demonstrated an unprecedented role of non-coding Alu transcribed elements in cancer progression. We found that Alu RNA induces epithelial-to-mesenchymal transition (EMT) acting as a molecular sponge for miR-566. Moreover, Alu RNA accumulates as a consequence of DICER1 deficit and its knockdown prevents DICER1 depletion-induced EMT despite global miRNA downregulation, introducing the novel concept that DICER1 function in cancer, as in other diseases, should be reconsidered in view of its role in the clearance of Alu RNA transcripts. Furthermore, TGF-β1, a major driver of EMT, also induced Alu RNA accumulation suggesting that Alu RNA is an important mediator of TGF-β1-driven EMT. Corroborating these data, we found that Alu RNA significantly accumulates in patient-matched human primary colorectal cancer tumors compared to normal tissue, and in patient-matched liver metastasis compared to primary tumors. The completion of this project will be of great general scientific relevance because a complete study of Alu RNA sequences in cancer was lacking in literature.The Researcher, Valeria Tarallo is now well integrated in the Host Institute as a staff Researcher since she got in September 2017 a permanent position and thanks to the CIG grant she is now independent and was able to built her own group that guarantee the transfer of knowledge. As integration activities she participated to the duties of the Host Institute, teaching in PhD courses and giving talks occasionally. The execution of the project is complying with the proposed objectives and timing.
