Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells.

Development of bone metastases is dependent on the cancer cell-bone cell interactions in the bone microenvironment. Transforming growth factor β (TGF-β) is released from bone during osteoclastic bone resorption and induces production of osteolytic factors, such as interleukin 11 (IL-11), in breast c...

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Autores principales:	Sirkku Pollari, Suvi-Katri Leivonen, Merja Perälä, Vidal Fey, Sanna-Maria Käkönen, Olli Kallioniemi
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f763dea29b8d4964b67cd0d09a3d260a
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spelling	oai:doaj.org-article:f763dea29b8d4964b67cd0d09a3d260a2021-11-18T07:17:56ZIdentification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells.1932-620310.1371/journal.pone.0037361https://doaj.org/article/f763dea29b8d4964b67cd0d09a3d260a2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22629385/?tool=EBIhttps://doaj.org/toc/1932-6203Development of bone metastases is dependent on the cancer cell-bone cell interactions in the bone microenvironment. Transforming growth factor β (TGF-β) is released from bone during osteoclastic bone resorption and induces production of osteolytic factors, such as interleukin 11 (IL-11), in breast cancer cells. IL-11 in turn increases osteolysis by stimulating osteoclast function, launching a vicious cycle of cancer growth and bone destruction. We aimed to identify and functionally characterize microRNAs (miRNAs) that mediate the bone metastatic process, focusing on miRNAs that regulate the TGF-β induction of IL-11. First, we profiled the expression of 455 miRNAs in a highly bone metastatic MDA-MB-231(SA) variant as compared to the parental MDA-MB-231 breast cancer cell line and found 16 miRNAs (3.5%) having a >3-fold expression difference between the two cell types. We then applied a cell-based overexpression screen with Pre-miRNA constructs to functionally identify miRNAs regulating TGF-β-induced IL-11 production. This analysis pinpointed miR-204, miR-211, and miR-379 as such key regulators. These miRNAs were shown to directly target IL11 by binding to its 3' UTR. MiR-379 also inhibited Smad2/3/4-mediated transcriptional activity. Gene expression analysis of miR-204 and miR-379-transfected cells indicated that these miRNAs downregulated the expression of several genes involved in TGF-β signaling, including prostaglandin-endoperoxide synthase 2 (PTGS2). In addition, there was a significant correlation between the genes downregulated by miR-379 and a set of genes upregulated in basal subtype of breast cancer. Taken together, the functional evidence and clinical correlations imply novel mechanistic links between miRNAs and the key steps in the bone metastatic process in breast cancer, with potential clinical relevance.Sirkku PollariSuvi-Katri LeivonenMerja PeräläVidal FeySanna-Maria KäkönenOlli KallioniemiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 5, p e37361 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sirkku Pollari Suvi-Katri Leivonen Merja Perälä Vidal Fey Sanna-Maria Käkönen Olli Kallioniemi Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells.
description	Development of bone metastases is dependent on the cancer cell-bone cell interactions in the bone microenvironment. Transforming growth factor β (TGF-β) is released from bone during osteoclastic bone resorption and induces production of osteolytic factors, such as interleukin 11 (IL-11), in breast cancer cells. IL-11 in turn increases osteolysis by stimulating osteoclast function, launching a vicious cycle of cancer growth and bone destruction. We aimed to identify and functionally characterize microRNAs (miRNAs) that mediate the bone metastatic process, focusing on miRNAs that regulate the TGF-β induction of IL-11. First, we profiled the expression of 455 miRNAs in a highly bone metastatic MDA-MB-231(SA) variant as compared to the parental MDA-MB-231 breast cancer cell line and found 16 miRNAs (3.5%) having a >3-fold expression difference between the two cell types. We then applied a cell-based overexpression screen with Pre-miRNA constructs to functionally identify miRNAs regulating TGF-β-induced IL-11 production. This analysis pinpointed miR-204, miR-211, and miR-379 as such key regulators. These miRNAs were shown to directly target IL11 by binding to its 3' UTR. MiR-379 also inhibited Smad2/3/4-mediated transcriptional activity. Gene expression analysis of miR-204 and miR-379-transfected cells indicated that these miRNAs downregulated the expression of several genes involved in TGF-β signaling, including prostaglandin-endoperoxide synthase 2 (PTGS2). In addition, there was a significant correlation between the genes downregulated by miR-379 and a set of genes upregulated in basal subtype of breast cancer. Taken together, the functional evidence and clinical correlations imply novel mechanistic links between miRNAs and the key steps in the bone metastatic process in breast cancer, with potential clinical relevance.
format	article
author	Sirkku Pollari Suvi-Katri Leivonen Merja Perälä Vidal Fey Sanna-Maria Käkönen Olli Kallioniemi
author_facet	Sirkku Pollari Suvi-Katri Leivonen Merja Perälä Vidal Fey Sanna-Maria Käkönen Olli Kallioniemi
author_sort	Sirkku Pollari
title	Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells.
title_short	Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells.
title_full	Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells.
title_fullStr	Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells.
title_full_unstemmed	Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells.
title_sort	identification of micrornas inhibiting tgf-β-induced il-11 production in bone metastatic breast cancer cells.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/f763dea29b8d4964b67cd0d09a3d260a
work_keys_str_mv	AT sirkkupollari identificationofmicrornasinhibitingtgfbinducedil11productioninbonemetastaticbreastcancercells AT suvikatrileivonen identificationofmicrornasinhibitingtgfbinducedil11productioninbonemetastaticbreastcancercells AT merjaperala identificationofmicrornasinhibitingtgfbinducedil11productioninbonemetastaticbreastcancercells AT vidalfey identificationofmicrornasinhibitingtgfbinducedil11productioninbonemetastaticbreastcancercells AT sannamariakakonen identificationofmicrornasinhibitingtgfbinducedil11productioninbonemetastaticbreastcancercells AT ollikallioniemi identificationofmicrornasinhibitingtgfbinducedil11productioninbonemetastaticbreastcancercells
_version_	1718423701740847104

Identification of microRNAs inhibiting TGF-β-induced IL-11 production in bone metastatic breast cancer cells.

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