MicroRNA-224 Induces G1/S Checkpoint Release in Liver Cancer

Profound changes in microRNA (miR) expression levels are frequently found in liver cancers compared to the normal liver. In this study, we evaluate the expression of miR-224 in human HCC and CCA, as well as its downstream targets and affected pathways. We show that miR-224 is upregulated in a large...

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Main Authors:	An, Fangmei, Olaru, Alexandru V., Mezey, Esteban, Xie, Qing, Li, Ling, Piontek, Klaus B., Selaru, Florin M.
Format:	Online
Language:	English
Published:	MDPI 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600154/

id	pubmed-4600154
recordtype	oai_dc
spelling	pubmed-46001542015-10-15 MicroRNA-224 Induces G1/S Checkpoint Release in Liver Cancer An, Fangmei Olaru, Alexandru V. Mezey, Esteban Xie, Qing Li, Ling Piontek, Klaus B. Selaru, Florin M. Article Profound changes in microRNA (miR) expression levels are frequently found in liver cancers compared to the normal liver. In this study, we evaluate the expression of miR-224 in human HCC and CCA, as well as its downstream targets and affected pathways. We show that miR-224 is upregulated in a large cohort of human CCA, similar to its upregulation in human HCC. For the purpose of studying the roles of miR-224 in HCC and CCA, we enforced miR-224 expression in cells. mRNA arrays followed by Ingenuity Pathway Analysis (IPA)-identified putative molecules and pathways downstream of miR-224. Phenotypically, we report that enforced expression of miR-224 increases the growth rate of normal cholangiocytes, CCA cell lines, and HCC cell lines. In addition, we identified, in an unbiased fashion, that one of the major biologic processes affected by miR-224 is Gap1 (G1) to Synthesis (S) transition checkpoint release. We next identified p21, p15, and CCNE1 as downstream targets of miR-224 and confirmed the coordinated downregulation results in the increased phosphorylation of Retinoblastoma (Rb) with resulting G1/S checkpoint release. Our data suggest that miR-224 is a master regulator of cell cycle progression, and that its overexpression results in G1/S checkpoint release followed by accelerated cell growth. MDPI 2015-08-26 /pmc/articles/PMC4600154/ /pubmed/26343737 http://dx.doi.org/10.3390/jcm4091713 Text en © 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	An, Fangmei Olaru, Alexandru V. Mezey, Esteban Xie, Qing Li, Ling Piontek, Klaus B. Selaru, Florin M.
spellingShingle	An, Fangmei Olaru, Alexandru V. Mezey, Esteban Xie, Qing Li, Ling Piontek, Klaus B. Selaru, Florin M. MicroRNA-224 Induces G1/S Checkpoint Release in Liver Cancer
author_facet	An, Fangmei Olaru, Alexandru V. Mezey, Esteban Xie, Qing Li, Ling Piontek, Klaus B. Selaru, Florin M.
author_sort	An, Fangmei
title	MicroRNA-224 Induces G1/S Checkpoint Release in Liver Cancer
title_short	MicroRNA-224 Induces G1/S Checkpoint Release in Liver Cancer
title_full	MicroRNA-224 Induces G1/S Checkpoint Release in Liver Cancer
title_fullStr	MicroRNA-224 Induces G1/S Checkpoint Release in Liver Cancer
title_full_unstemmed	MicroRNA-224 Induces G1/S Checkpoint Release in Liver Cancer
title_sort	microrna-224 induces g1/s checkpoint release in liver cancer
description	Profound changes in microRNA (miR) expression levels are frequently found in liver cancers compared to the normal liver. In this study, we evaluate the expression of miR-224 in human HCC and CCA, as well as its downstream targets and affected pathways. We show that miR-224 is upregulated in a large cohort of human CCA, similar to its upregulation in human HCC. For the purpose of studying the roles of miR-224 in HCC and CCA, we enforced miR-224 expression in cells. mRNA arrays followed by Ingenuity Pathway Analysis (IPA)-identified putative molecules and pathways downstream of miR-224. Phenotypically, we report that enforced expression of miR-224 increases the growth rate of normal cholangiocytes, CCA cell lines, and HCC cell lines. In addition, we identified, in an unbiased fashion, that one of the major biologic processes affected by miR-224 is Gap1 (G1) to Synthesis (S) transition checkpoint release. We next identified p21, p15, and CCNE1 as downstream targets of miR-224 and confirmed the coordinated downregulation results in the increased phosphorylation of Retinoblastoma (Rb) with resulting G1/S checkpoint release. Our data suggest that miR-224 is a master regulator of cell cycle progression, and that its overexpression results in G1/S checkpoint release followed by accelerated cell growth.
publisher	MDPI
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600154/
_version_	1613486070127656960

MicroRNA-224 Induces G1/S Checkpoint Release in Liver Cancer

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