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Clinical Breast Cancer June 2019 - 215 Original Article
Axl-Targeted Delivery of the Oncosuppressor miR-137 in Non-small-Cell Lung Cancer
Silvia Nuzzo,1,8 Silvia Catuogno,2,8 Maria Capuozzo,2 Alfonso Fiorelli,3 Piotr Swiderski,4 Serena Boccella,5 Filomena de Nigris,6,7 and Carla Lucia Esposito2
1IRCCS SDN, Naples, Italy; 2Istituto di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (CNR), Naples, Italy; 3Thoracic Surgery Unit, University of Campania “Luigi Vanvitelli,” Naples, Italy; 4DNA/RNA Synthesis Laboratory, Beckman Research Institute of City the of Hope, Duarte, CA, USA; 5Department of Experimental Medicine, University of Campania “Luigi Vanvitelli,” Naples, Italy; 6Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” Naples, Italy; 7Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
Non-small-cell lung cancer (NSCLC) accounts for 85%–90% of all cases of lung cancer that is the most deadly type of cancer. Despite advances in chemotherapy and radiotherapy, severe side effects and frequent drug resistance limit the success of the treatments, and the identification of new therapeutic options still represents a crucial challenge. Here, we provide the evidence for the therapeutic potential of an aptamer-micro-RNA (miR) complex (AmiC) composed by an aptamer (GL21.T), able to bind and antagonize the oncogenic receptor Axl, and the miR-137, downregulated in lung cancer and involved in cell survival and proliferation. We found that, when applied to Axl-expressing NSCLC cancer cells, the com-plex is effectively internalized, increasing miR cellular levels and downregulating miR targets. Most importantly, the com-plex combines the inhibitory function of the GL21.T aptamer and miR-137, leading to a negative impact on NSCLC migra-tion and growth. The described AmiC thus represents a prom-ising tool for the development of new therapeutic approaches for NSCLC.
Lung cancer is the leading cause of cancer-related death in the world, with non-small-cell lung cancer (NSCLC) representing approxi-mately 80% of all lung cancer.1,2 Median survival time of patients with NSCLC after diagnosis is generally less than 1 year. In addition, NSCLC cells often retain the ability to evade drug-induced death signals, and relapses are frequent.3 Thus, the identification of new therapeutic options is a crucial challenge in oncology.
MicroRNAs (miRs) are short non-coding RNAs that regulate gene expression by causing either inhibition of mRNA translation into proteins and/or mRNA degradation.4 They are emerging as prom-ising therapeutic tools for cancer therapy.5 Among other miRs, miR-137 has been found to be downregulated and to act as a tumor suppressor in several cancers, including NSCLC. It has been demon-strated that a high miR-137 expression correlates with a higher NSCLC patient survival6 and that it regulates cell proliferation and tumor growth.7–9
Despite their therapeutic potential, miRs’ specific delivery to tumor cells still represents an essential step for their clinical development. In recent years, great hope for the selective delivery of miRs has emerged from the use of nucleic acid aptamers as targeting agents. They are high-affinity ligands and potential antagonists of disease-associated proteins and have many advantages as therapeutic agents and effective delivery carriers for the specific and safe diffusion of secondary reagents into tumor cells.10 Several studies have demon-strated the broad applicability both in vitro and in vivo of aptamer-mediated delivery of therapeutic small interfering RNAs (siRNAs) and miRs.11–18 In previous studies, we reported the generation of 20-fluoropyrimidine (20F-Py) nuclease-resistant RNA aptamer, named GL21.T, binding and antagonizing the oncogenic receptor
tyrosine kinase Axl.19 We showed that GL21.T can be used for the se-lective delivery to Axl+ cells of therapeutic miR-based molecules.16,17