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Theranostics 2018; 8(4):1106-1120. doi:10.7150/thno.19904 This issue Cite

Research Paper

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

Xin Lai^1*✉, Shailendra K Gupta^2,6*, Ulf Schmitz^3,4*, Stephan Marquardt⁵, Susanne Knoll⁵, Alf Spitschak⁵, Olaf Wolkenhauer^{2,7# ✉}, Brigitte M Pützer^5#, Julio Vera^1#✉

1. Laboratory of Systems Tumour Immunology, Department of Dermatology, Friedrich-Alexander-University of Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany;
2. Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany;
3. Gene & Stem Cell Therapy Program, Centenary Institute, University of Sydney, Camperdown, Australia;
4. Sydney Medical School, University of Sydney, Camperdown, Australia;
5. Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Centre, Rostock, Germany;
6. CSIR-Indian Institute of Toxicology Research, Lucknow, India;
7. Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Stellenbosch, South Africa.
* Equal first authors
# Equal senior contributors

✉ Corresponding authors: Xin Lai, Tel: +49(0)91318545888, Fax: +49(0)91318533874, Email: xin.laide; Julio Vera, Tel: +49(0)91318545888, Fax: +49(0)91318533874, Email: julio.vera-gonzalezde; Olaf Wolkenhauer, Tel: +49(0)3814987570, Fax: +49(0)3814987572, Email: olaf.wolkenhauerde More

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.

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