Papel de la quinasa humana VRK1 en la biología del neuroblastoma

Résumé

Neuroblastoma is the most common solid extracranial tumor in childhood with a very heterogeneous behavior, ranging from spontaneous regression to very aggressive metastatic tumors. One of the most used prognostic factors to date is the amplification of the MYCN oncogene, which is indicative of low survival, Although, given the low survival of patients with aggressive versions of the disease, the identification of new expected factors and the development of therapeutic tools. Among the issues to be elucidated, is the possible implication of the so-called cancer stem cells at the origin and tumor progression. The objective of this doctoral thesis project has been to study the role of human kinase VRK1 in the most aggressive neuroblastomas, and its possible involvement in cancerous stem cell populations. To study the expression of said protein and its association with tumor malignancy, we make use of data from neuroblastoma tumors, human tumor samples and cell lines. Through different laboratory techniques, we have analyzed their expression, gene and protein, and studied their function, in addition to specifically silencing their expression to perform functional tests in vitro and in vivo in NB models. The results indicate that the VRK1 protein is highly expressed in the most aggressive neuroblastoma tumors, having predictive value even in nonamplified MYCN tumors. We have also analyzed the expression of this protein in neuroblastoma progenitor cells and have found a relationship between VRK1 and proliferation in this type of cell population. In addition, a reduction in the expression of this kinase in cancer cells causes a stop in the cell cycle, greater differentiation and sensitivity to treatment. We believe that the work presented here lays the groundwork for a more detailed study on a possible new therapeutic use in this complicated childhood cancer.