Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model

Abstract Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a potent inhibitor of matrix metalloproteinases (MMPs) is a common negative target of oncogenic signals and a potential therapeutic target for novel drug development. Here, we show that sequential RECKlessness stimulates ang...

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Autores principales:	Jaganathan Kowshik, Rajakishore Mishra, Josephraj Sophia, Satabdi Rautray, Kumaraswamy Anbarasu, G. Deepak Reddy, Madhulika Dixit, Sundarasamy Mahalingam, Siddavaram Nagini
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2e5292f5a45a4f54a69126fff9216ca9
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spelling	oai:doaj.org-article:2e5292f5a45a4f54a69126fff9216ca92021-12-02T16:06:14ZNimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model10.1038/s41598-017-01960-52045-2322https://doaj.org/article/2e5292f5a45a4f54a69126fff9216ca92017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01960-5https://doaj.org/toc/2045-2322Abstract Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a potent inhibitor of matrix metalloproteinases (MMPs) is a common negative target of oncogenic signals and a potential therapeutic target for novel drug development. Here, we show that sequential RECKlessness stimulates angiogenesis and Notch signalling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model, a paradigm for oral oncogenesis and chemointervention. We also report the chemotherapeutic effect of nimbolide, a limonoid from the neem tree (Azadirachta indica) based on the upregulation of RECK as well as modulation of the expression of key molecules involved in invasion and angiogenesis. We demonstrate that nimbolide upregulates RECK by targeting miR-21, and HIF-1α resulting in reduced MMP activity and blockade of VEGF and Notch signalling. Nimbolide reduced microvascular density, confirming its anti-angiogenic potential. Molecular docking analysis revealed interaction of nimbolide with HIF-1α. Additionally, we demonstrate that nimbolide upregulates RECK expression via downregulation of HIF-1α and miR-21 by overexpression and knockdown experiments in SCC4 and EAhy926 cell lines. Taken together, these findings provide compelling evidence that targeting RECK, a keystone protein that regulates mediators of invasion and angiogenesis with phytochemicals such as nimbolide may be a robust therapeutic approach to prevent oral cancer progression.Jaganathan KowshikRajakishore MishraJosephraj SophiaSatabdi RautrayKumaraswamy AnbarasuG. Deepak ReddyMadhulika DixitSundarasamy MahalingamSiddavaram NaginiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jaganathan Kowshik Rajakishore Mishra Josephraj Sophia Satabdi Rautray Kumaraswamy Anbarasu G. Deepak Reddy Madhulika Dixit Sundarasamy Mahalingam Siddavaram Nagini Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model
description	Abstract Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a potent inhibitor of matrix metalloproteinases (MMPs) is a common negative target of oncogenic signals and a potential therapeutic target for novel drug development. Here, we show that sequential RECKlessness stimulates angiogenesis and Notch signalling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model, a paradigm for oral oncogenesis and chemointervention. We also report the chemotherapeutic effect of nimbolide, a limonoid from the neem tree (Azadirachta indica) based on the upregulation of RECK as well as modulation of the expression of key molecules involved in invasion and angiogenesis. We demonstrate that nimbolide upregulates RECK by targeting miR-21, and HIF-1α resulting in reduced MMP activity and blockade of VEGF and Notch signalling. Nimbolide reduced microvascular density, confirming its anti-angiogenic potential. Molecular docking analysis revealed interaction of nimbolide with HIF-1α. Additionally, we demonstrate that nimbolide upregulates RECK expression via downregulation of HIF-1α and miR-21 by overexpression and knockdown experiments in SCC4 and EAhy926 cell lines. Taken together, these findings provide compelling evidence that targeting RECK, a keystone protein that regulates mediators of invasion and angiogenesis with phytochemicals such as nimbolide may be a robust therapeutic approach to prevent oral cancer progression.
format	article
author	Jaganathan Kowshik Rajakishore Mishra Josephraj Sophia Satabdi Rautray Kumaraswamy Anbarasu G. Deepak Reddy Madhulika Dixit Sundarasamy Mahalingam Siddavaram Nagini
author_facet	Jaganathan Kowshik Rajakishore Mishra Josephraj Sophia Satabdi Rautray Kumaraswamy Anbarasu G. Deepak Reddy Madhulika Dixit Sundarasamy Mahalingam Siddavaram Nagini
author_sort	Jaganathan Kowshik
title	Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model
title_short	Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model
title_full	Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model
title_fullStr	Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model
title_full_unstemmed	Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model
title_sort	nimbolide upregulates reck by targeting mir-21 and hif-1α in cell lines and in a hamster oral carcinogenesis model
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/2e5292f5a45a4f54a69126fff9216ca9
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Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model

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