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Loss of miR-10a Activates Lpo and Collaborates with Activated Wnt Signaling in Inducing Intestinal Neoplasia in Female Mice

miRNAs are small regulatory RNAs that, due to their considerable potential to target a wide range of mRNAs, are implicated in essentially all biological process, including cancer. miR-10a is particularly interesting considering its conserved location in the Hox cluster of developmental regulators. A...

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Autores principales: Stadthagen, Gustavo, Tehler, Disa, Høyland-Kroghsbo, Nina Molin, Wen, Jiayu, Krogh, Anders, Jensen, Klaus T., Santoni-Rugiu, Eric, Engelholm, Lars H., Lund, Anders H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812087/
https://www.ncbi.nlm.nih.gov/pubmed/24204315
http://dx.doi.org/10.1371/journal.pgen.1003913
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author Stadthagen, Gustavo
Tehler, Disa
Høyland-Kroghsbo, Nina Molin
Wen, Jiayu
Krogh, Anders
Jensen, Klaus T.
Santoni-Rugiu, Eric
Engelholm, Lars H.
Lund, Anders H.
author_facet Stadthagen, Gustavo
Tehler, Disa
Høyland-Kroghsbo, Nina Molin
Wen, Jiayu
Krogh, Anders
Jensen, Klaus T.
Santoni-Rugiu, Eric
Engelholm, Lars H.
Lund, Anders H.
author_sort Stadthagen, Gustavo
collection PubMed
description miRNAs are small regulatory RNAs that, due to their considerable potential to target a wide range of mRNAs, are implicated in essentially all biological process, including cancer. miR-10a is particularly interesting considering its conserved location in the Hox cluster of developmental regulators. A role for this microRNA has been described in developmental regulation as well as for various cancers. However, previous miR-10a studies are exclusively based on transient knockdowns of this miRNA and to extensively study miR-10a loss we have generated a miR-10a knock out mouse. Here we show that, in the Apc(min) mouse model of intestinal neoplasia, female miR-10a deficient mice develop significantly more adenomas than miR-10(+/+) and male controls. We further found that Lpo is extensively upregulated in the intestinal epithelium of mice deprived of miR-10a. Using in vitro assays, we demonstrate that the primary miR-10a target KLF4 can upregulate transcription of Lpo, whereas siRNA knockdown of KLF4 reduces LPO levels in HCT-116 cells. Furthermore, Klf4 is upregulated in the intestines of miR-10a knockout mice. Lpo has previously been shown to have the capacity to oxidize estrogens into potent depurinating mutagens, creating an instable genomic environment that can cause initiation of cancer. Therefore, we postulate that Lpo upregulation in the intestinal epithelium of miR-10a deficient mice together with the predominant abundance of estrogens in female animals mainly accounts for the sex-related cancer phenotype we observed. This suggests that miR-10a could be used as a potent diagnostic marker for discovering groups of women that are at high risk of developing colorectal carcinoma, which today is one of the leading causes of cancer-related deaths.
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spelling pubmed-38120872013-11-07 Loss of miR-10a Activates Lpo and Collaborates with Activated Wnt Signaling in Inducing Intestinal Neoplasia in Female Mice Stadthagen, Gustavo Tehler, Disa Høyland-Kroghsbo, Nina Molin Wen, Jiayu Krogh, Anders Jensen, Klaus T. Santoni-Rugiu, Eric Engelholm, Lars H. Lund, Anders H. PLoS Genet Research Article miRNAs are small regulatory RNAs that, due to their considerable potential to target a wide range of mRNAs, are implicated in essentially all biological process, including cancer. miR-10a is particularly interesting considering its conserved location in the Hox cluster of developmental regulators. A role for this microRNA has been described in developmental regulation as well as for various cancers. However, previous miR-10a studies are exclusively based on transient knockdowns of this miRNA and to extensively study miR-10a loss we have generated a miR-10a knock out mouse. Here we show that, in the Apc(min) mouse model of intestinal neoplasia, female miR-10a deficient mice develop significantly more adenomas than miR-10(+/+) and male controls. We further found that Lpo is extensively upregulated in the intestinal epithelium of mice deprived of miR-10a. Using in vitro assays, we demonstrate that the primary miR-10a target KLF4 can upregulate transcription of Lpo, whereas siRNA knockdown of KLF4 reduces LPO levels in HCT-116 cells. Furthermore, Klf4 is upregulated in the intestines of miR-10a knockout mice. Lpo has previously been shown to have the capacity to oxidize estrogens into potent depurinating mutagens, creating an instable genomic environment that can cause initiation of cancer. Therefore, we postulate that Lpo upregulation in the intestinal epithelium of miR-10a deficient mice together with the predominant abundance of estrogens in female animals mainly accounts for the sex-related cancer phenotype we observed. This suggests that miR-10a could be used as a potent diagnostic marker for discovering groups of women that are at high risk of developing colorectal carcinoma, which today is one of the leading causes of cancer-related deaths. Public Library of Science 2013-10-24 /pmc/articles/PMC3812087/ /pubmed/24204315 http://dx.doi.org/10.1371/journal.pgen.1003913 Text en © 2013 Stadthagen et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Stadthagen, Gustavo
Tehler, Disa
Høyland-Kroghsbo, Nina Molin
Wen, Jiayu
Krogh, Anders
Jensen, Klaus T.
Santoni-Rugiu, Eric
Engelholm, Lars H.
Lund, Anders H.
Loss of miR-10a Activates Lpo and Collaborates with Activated Wnt Signaling in Inducing Intestinal Neoplasia in Female Mice
title Loss of miR-10a Activates Lpo and Collaborates with Activated Wnt Signaling in Inducing Intestinal Neoplasia in Female Mice
title_full Loss of miR-10a Activates Lpo and Collaborates with Activated Wnt Signaling in Inducing Intestinal Neoplasia in Female Mice
title_fullStr Loss of miR-10a Activates Lpo and Collaborates with Activated Wnt Signaling in Inducing Intestinal Neoplasia in Female Mice
title_full_unstemmed Loss of miR-10a Activates Lpo and Collaborates with Activated Wnt Signaling in Inducing Intestinal Neoplasia in Female Mice
title_short Loss of miR-10a Activates Lpo and Collaborates with Activated Wnt Signaling in Inducing Intestinal Neoplasia in Female Mice
title_sort loss of mir-10a activates lpo and collaborates with activated wnt signaling in inducing intestinal neoplasia in female mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812087/
https://www.ncbi.nlm.nih.gov/pubmed/24204315
http://dx.doi.org/10.1371/journal.pgen.1003913
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