De Martino, Marco (2017) HMGA1 pseudogenes as oncogenic competitive endogenous RNAs. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: HMGA1 pseudogenes as oncogenic competitive endogenous RNAs
Creators:
CreatorsEmail
De Martino, Marcomarco.demartino2@unina.it
Date: 2017
Number of Pages: 106
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Dottorato: Medicina molecolare e biotecnologie mediche
Ciclo di dottorato: 29
Coordinatore del Corso di dottorato:
nomeemail
Avvedimento, Enrico Vittorioavvedim@unina.it
Tutor:
nomeemail
Fusco, AlfredoUNSPECIFIED
Esposito, FrancescoUNSPECIFIED
Date: 2017
Number of Pages: 106
Uncontrolled Keywords: HMGA1, pseudogene, ceRNA, cancer
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/04 - Patologia generale
Date Deposited: 03 May 2017 08:47
Last Modified: 13 Mar 2018 11:24
URI: http://www.fedoa.unina.it/id/eprint/11546
DOI: 10.6093/UNINA/FEDOA/11546

Abstract

The High Mobility Group A family is composed of non-histone chromosomal proteins that orchestrate the assembly of the nucleoprotein complexes involved in gene transcription, replication, and chromatin structure. HMGA1 overexpression is a feature of human cancer, and has a causal role in cell transformation. However, the molecular basis of this upregulation has not been completely elucidated. The identification and validation of numerous HMGA1-targeting microRNAs demonstrates that cells are sensitive to even subtle increases in HMGA1 abundance, thus highlighting the importance of microRNA-mediated HMGA1 regulation in cancer. Pseudogenes have long been considered as non-functional genomic sequences. However, recent evidence suggests that many of them might have some form of biological activity, and the possibility of functionality through a microRNA-mediated pathway. In fact, recent studies show that microRNAs could act as a regulatory language, through which messenger RNAs, transcribed pseudogenes, and long non-coding RNAs crosstalk with each other and form a previously unknown regulatory network. RNA transcripts involved in this network have been termed “competitive endogenous RNAs”, since they influence each other's level by competing for the same pool of microRNAs through microRNA response elements on their target transcripts. Our research group identified two HMGA1 pseudogene-derived RNA transcripts, HMGA1P6 and HMGA1P7, that competing with HMGA1 for microRNA binding, lead to the upregulation of HMGA1 cellular levels, exerting an oncogenic role. We demonstrate that the overexpression of these HMGA1 pseudogenes increases the levels of HMGA1 and other cancer- related genes by inhibiting the suppression of their synthesis mediated by microRNAs. Moreover, HMGA1 pseudogenes were found overexpressed in several human cancer types. Interestingly, preliminary results showed that mice engineered to overexpress HMGA1P6 or HMGA1P7 develop malignant B cell lymphomas. Therefore, the HMGA1-pseudogene engineered mouse models demonstrate the oncogenic potential of these pseudogenes and indicate that ceRNA-mediated microRNA sequestration may contribute to the development of cancer.

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