miRNA:mRNA interplay in the malignant evolution of miniGIST to overt GIST

Gastrointestinal Stromal Tumor (GIST) is the most common mesenchymal tumor that occurs throughout the digestive tract and is thought to arise from the gastrointestinal (GI) pacemakers, the Interstitial Cells of Cajal (ICC). Different from most sarcomas for which premalignant lesions are not known, premalignant GIST counterparts have been identified. These entities, named miniGIST, share with overt GIST histological and molecular features, namely the presence of oncogenic mutations affecting the tyrosine kinases KIT or PDGFRA. MiniGISTs are remarkably common (about 1/3 of unselected elderly subjects carry miniGIST in their GI tract) whilst GIST are quite rare, indicating that a very minute fraction of miniGIST actually progress to clinically relevant tumors. This indicates that KIT/PDGFRA oncogenic mutations are insufficient to convey malignancy. The aim of this work was to address the molecular mechanisms that sustain miniGIST to overt GIST malignant evolution, focusing on particular on the role of miRNAs. By performing combined miRNA and mRNA NGS profilings of a large set of miniGISTs and overt GISTs we identified a set of miRNAs potentially involved in the transcriptional perturbation during GIST progression. We made a step ahead by in vitro validating the role of hsa-miR-485-5p loss in determining the BIRC5 gene upregulation in overt GIST. Overall, our work laid down the bases for the elucidation of the role of miRNA:mRNA interaction in the malignant evolution of GIST.