MiR-205-5p and miR-342-3p cooperate in the repression of the E2F1 transcription factor in the context of anticancer chemotherapy resistance

MiR-205-5p and miR-342-3p cooperate in the repression of the E2F1 transcription factor in the context of anticancer chemotherapy resistance.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.7150/thno.19904
Journal or Publication Title: Theranostics
Volume: 8
Number: 4
Page Range: pp. 1106-1120
Date: 2018
Divisions: Computational BioMedicine
Depositing User: General Admin
Identification Number: 10.7150/thno.19904
ISSN: 1838-7640
Date Deposited: 04 Jan 2021 23:26
Abstract:

High rates of lethal outcome in tumour metastasis are associated with the acquisition of invasiveness and chemoresistance. Several clinical studies indicate that E2F1 overexpression across high-grade tumours culminates in unfavourable prognosis and chemoresistance in patients. Thus, fine-tuning the expression of E2F1 could be a promising approach for treating patients showing chemoresistance.

Methods: We integrated bioinformatics, structural and kinetic modelling, and experiments to study cooperative regulation of E2F1 by microRNA (miRNA) pairs in the context of anticancer chemotherapy resistance.

Results: We showed that an enhanced E2F1 repression efficiency can be achieved in chemoresistant tumour cells through two cooperating miRNAs. Sequence and structural information were used to identify potential miRNA pairs that can form tertiary structures with E2F1 mRNA. We then employed molecular dynamics simulations to show that among the identified triplexes, miR-205-5p and miR-342-3p can form the most stable triplex with E2F1 mRNA. A mathematical model simulating the E2F1 regulation by the cooperative miRNAs predicted enhanced E2F1 repression, a feature that was verified by in vitro experiments. Finally, we integrated this cooperative miRNA regulation into a more comprehensive network to account for E2F1-related chemoresistance in tumour cells. The network model simulations and experimental data indicate the ability of enhanced expression of both miR-205-5p and miR-342-3p to decrease tumour chemoresistance by cooperatively repressing E2F1.

Conclusions: Our results suggest that pairs of cooperating miRNAs could be used as potential RNA therapeutics to reduce E2F1-related chemoresistance.

Keywords: MicroRNA, E2F1, Chemotherapy resistance, Molecular dynamics simulation, Kinetic modelling.

Creators:
Creators
Email
Lai, Xin
UNSPECIFIED
Gupta, Shailendra K
UNSPECIFIED
Schmitz, Ulf
UNSPECIFIED
Marquardt, Stephan
UNSPECIFIED
Knoll, Susanne
UNSPECIFIED
Spitschak, Alf
UNSPECIFIED
Wolkenhauer, Olaf
UNSPECIFIED
Pützer, Brigitte M
UNSPECIFIED
Vera, Julio
UNSPECIFIED
Last Modified: 04 Jan 2021 23:26
URI: https://eprints.centenary.org.au/id/eprint/580

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