Integrative microRNA and gene expression analysis identifies new epigenetically regulated microRNAs mediating taxane resistance in ovarian cancer

Abstract Taxane is a family of front-line chemotherapeutic agents against ovarian cancer (OC). The therapeutic efficacy is frequently counteracted by the development of chemoresistance, leading to high rates of relapse in OC patients. The role(s) of microRNAs (miRNAs) in cancer chemoresistance had b...

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Autores principales:	Mohamed K. Hassan, Amr A. Waly, Waheba Elsayed, Sarah Keshk, Walaa Ramadan Allam, Sherif F. El-khamisy
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4e3629cb503e4e85af2738dd807c0589
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spelling	oai:doaj.org-article:4e3629cb503e4e85af2738dd807c05892021-12-02T14:12:43ZIntegrative microRNA and gene expression analysis identifies new epigenetically regulated microRNAs mediating taxane resistance in ovarian cancer10.1038/s41598-020-78596-52045-2322https://doaj.org/article/4e3629cb503e4e85af2738dd807c05892021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78596-5https://doaj.org/toc/2045-2322Abstract Taxane is a family of front-line chemotherapeutic agents against ovarian cancer (OC). The therapeutic efficacy is frequently counteracted by the development of chemoresistance, leading to high rates of relapse in OC patients. The role(s) of microRNAs (miRNAs) in cancer chemoresistance had been supported by many evidences Epigenetic regulation by miRNAs has been reported to influence cancer development and response to therapeutics, however, their role in OC resistance to paclitaxel (PTX) is unclear. Here, we conducted miRNA profiling in the responsive and PTX-resistant OC cell lines before and after treatment with epigenetic modulators. We reveal 157 miRNAs to be downregulated in the PTX-resistant cells compared to parental controls. The expression of five miRNAs (miRNA-7-5p, -204-3p, -501-5p, -3652 and -4286) was restored after epigenetic modulation, which was further confirmed by qPCR. In silico analysis of the signaling pathways targeted by the selected miRNAs identified the PI3K-AKT pathway as the primary target. Subsequent cDNA array analysis confirmed multiple PI3K-AKT pathway members such as AKT2, PIK3R3, CDKN1A, CCND2 and FGF2 to be upregulated in PTX-resistant cells. STRING analysis showed the deregulated genes in PTX-resistant cells to be primarily involved in cell cycle progression and survival. Thus, high throughput miRNA and cDNA profiling coupled with pathway analysis and data mining provide evidence for epigenetically regulated miRNAs-induced modulation of signaling pathways in PTX resistant OC cells. It paves the way to more in-depth mechanistic studies and new therapeutic strategies to combat chemoresistance.Mohamed K. HassanAmr A. WalyWaheba ElsayedSarah KeshkWalaa Ramadan AllamSherif F. El-khamisyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mohamed K. Hassan Amr A. Waly Waheba Elsayed Sarah Keshk Walaa Ramadan Allam Sherif F. El-khamisy Integrative microRNA and gene expression analysis identifies new epigenetically regulated microRNAs mediating taxane resistance in ovarian cancer
description	Abstract Taxane is a family of front-line chemotherapeutic agents against ovarian cancer (OC). The therapeutic efficacy is frequently counteracted by the development of chemoresistance, leading to high rates of relapse in OC patients. The role(s) of microRNAs (miRNAs) in cancer chemoresistance had been supported by many evidences Epigenetic regulation by miRNAs has been reported to influence cancer development and response to therapeutics, however, their role in OC resistance to paclitaxel (PTX) is unclear. Here, we conducted miRNA profiling in the responsive and PTX-resistant OC cell lines before and after treatment with epigenetic modulators. We reveal 157 miRNAs to be downregulated in the PTX-resistant cells compared to parental controls. The expression of five miRNAs (miRNA-7-5p, -204-3p, -501-5p, -3652 and -4286) was restored after epigenetic modulation, which was further confirmed by qPCR. In silico analysis of the signaling pathways targeted by the selected miRNAs identified the PI3K-AKT pathway as the primary target. Subsequent cDNA array analysis confirmed multiple PI3K-AKT pathway members such as AKT2, PIK3R3, CDKN1A, CCND2 and FGF2 to be upregulated in PTX-resistant cells. STRING analysis showed the deregulated genes in PTX-resistant cells to be primarily involved in cell cycle progression and survival. Thus, high throughput miRNA and cDNA profiling coupled with pathway analysis and data mining provide evidence for epigenetically regulated miRNAs-induced modulation of signaling pathways in PTX resistant OC cells. It paves the way to more in-depth mechanistic studies and new therapeutic strategies to combat chemoresistance.
format	article
author	Mohamed K. Hassan Amr A. Waly Waheba Elsayed Sarah Keshk Walaa Ramadan Allam Sherif F. El-khamisy
author_facet	Mohamed K. Hassan Amr A. Waly Waheba Elsayed Sarah Keshk Walaa Ramadan Allam Sherif F. El-khamisy
author_sort	Mohamed K. Hassan
title	Integrative microRNA and gene expression analysis identifies new epigenetically regulated microRNAs mediating taxane resistance in ovarian cancer
title_short	Integrative microRNA and gene expression analysis identifies new epigenetically regulated microRNAs mediating taxane resistance in ovarian cancer
title_full	Integrative microRNA and gene expression analysis identifies new epigenetically regulated microRNAs mediating taxane resistance in ovarian cancer
title_fullStr	Integrative microRNA and gene expression analysis identifies new epigenetically regulated microRNAs mediating taxane resistance in ovarian cancer
title_full_unstemmed	Integrative microRNA and gene expression analysis identifies new epigenetically regulated microRNAs mediating taxane resistance in ovarian cancer
title_sort	integrative microrna and gene expression analysis identifies new epigenetically regulated micrornas mediating taxane resistance in ovarian cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4e3629cb503e4e85af2738dd807c0589
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Integrative microRNA and gene expression analysis identifies new epigenetically regulated microRNAs mediating taxane resistance in ovarian cancer

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