Functional analysis of miRNAs and search for new targets of adrenocortical tumor in children and adolescents

Abstract

MicroRNAs (miRNAs) are small noncoding single-stranded molecules that function as regulators of mRNAs through translational repression in a manner sequence-specific. Therefore the search for sequence-specific targets of microRNAs is a major area of research, especially in cancer. It is known that some miRNAs (oncomirs) targets oncogenes and its loss enhances the expression of the related oncogenes. In an opposite way increased expression of those oncomirs acts as tumor repressor through regulation of target oncogenes. Understand the functions of miRNAs are, therefore, crucial to unveil this form of gene regulation and to harness this knowledge for therapeutic benefit in cancer. It is known that the adrenocortical tumor (ACTs), although rare in childhood, has a high mortality rate in more advanced stages. But the identification of malignant and benign forms still difficult to evaluate without morphological and histological analysis. Also there are no reliable molecular markers that can help to distinguish between them. In our work we found miRNAs differentially expressed between tumor and non-neoplastic tissues, also in patients with unfavorable prognosis stage IV and patients with relapsed/metastatic tumors. In this second step, we propose to perform in silico analysis, functional assays to test candidates miRNAs and elucidate the intracellular pathways regulated by these miRNAs in collaboration with Dr. Silvio Gutkind and Dr. Patricia Dillenburg Pilla, NIH (National Institutes of Health), Bethesda, USA. This laboratory mastered various techniques of functional analysis of animal and human tumor cells. We believe that the data generated from the development of this project will contribute significantly to the understanding of the mechanisms of action of miRNAs in tumor biology, especially the adrenal tumors. For many of these miRNAs the mechanisms and targets is still not yet known, therefore, unravel the mechanisms of action of these miRNAs, will allow the use of them for diagnostic, prognostic or even as therapeutic targets providing the basis for developing new drugs. (AU)