Russo, Valentina (2016) Innovative therapies based on the use of non-coding RNAs for non-small cell lung cancer (NSCLC). [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: Innovative therapies based on the use of non-coding RNAs for non-small cell lung cancer (NSCLC)
Creators:
CreatorsEmail
Russo, Valentinavalentina.russo86@alice.it
Date: 31 March 2016
Number of Pages: 111
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Scuola di dottorato: Biotecnologie
Dottorato: Patologia e fisiopatologia molecolare
Ciclo di dottorato: 28
Coordinatore del Corso di dottorato:
nomeemail
Avvedimento, Vittorio Enricoavvedim@unina.it
Tutor:
nomeemail
Condorelli, GerolamaUNSPECIFIED
Date: 31 March 2016
Number of Pages: 111
Uncontrolled Keywords: miRNA; aptamer; non-small cell lung cancer; cancer therapy
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/11 - Biologia molecolare
Area 06 - Scienze mediche > MED/04 - Patologia generale
Date Deposited: 13 Apr 2016 10:35
Last Modified: 05 May 2017 01:00
URI: http://www.fedoa.unina.it/id/eprint/10855

Abstract

Recent studies have shown the importance of microRNAs (miRNAs) as key regulators in several human disease, and also their great potential as new class of therapeutics cancer therapeutics. However, a major obstacle to their translation to clinic is actually represented by the lack of a robust and reliable way to selectively deliver them to the target malignant tumor cells. Today, nucleic-acid aptamers represent an expanding new class of biomolecules which is revealing as an interesting and highly promising for the specific delivery of RNA-based therapeutics. In this study, I intend to validate the use of aptamers as cell-specific delivery molecules for “therapeutic” miRNAs. I identified a tumor-suppressive miRNA in non-small cell lung cancer (NSCLC), miR-34c. I demonstrated that the expression of miR-34c is low in NCSCL and when transfected into cell lines is able to impact on cell survival. By applying methods successfully used in our laboratory, I conjugated the tumor-suppressor miR-34c to a nucleic acid aptamer, that selectively recognizes the AXL receptor and is rapidly internalized (GL21.T), generating a “molecular chimera”. With sticky-end annealing, the aptamer and a single chain anti-miRNA (or the passenger strand of the miRNA) are annealed by the mean of complementary sticky ends elongated at the 3’ end of the aptamer and at the 5’ end of the single chain of the miRNA, respectively. I demonstrated that the GL21.T/miR-34c chimera is able to bind and to carry the miRNA within the NSCLC cells. Interestingly, I demonstrated that a miR-34c target is the AXL receptor. Thus, the GL21.T/miR-34c chimera is able to exert a dual inhibition of AXL, either at functional or at transcriptional level. Finally, I evaluated the functional effects of the chimera in NSCLC cells that selectively express AXL receptor.

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