Retrotransposition of Long Interspersed Nucleotide Element-1 Is Associated with Colitis but Not Tumors in a Murine Colitic Cancer Model

Long interspersed element-1 (L1) is a transposable element that can move within the genome, potentially leading to genome diversity and modified gene function. Although L1 activity in somatic cells is normally suppressed through DNA methylation, some L1s are activated in tumors including colorectal...

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Autores principales: Otsubo, Takeshi, Okamura, Tadashi, Hagiwara, Teruki, Ishizaka, Yukihito, Dohi, Taeko, Kawamura, Yuki I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339839/
https://www.ncbi.nlm.nih.gov/pubmed/25710700
http://dx.doi.org/10.1371/journal.pone.0116072
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author Otsubo, Takeshi
Okamura, Tadashi
Hagiwara, Teruki
Ishizaka, Yukihito
Dohi, Taeko
Kawamura, Yuki I.
author_facet Otsubo, Takeshi
Okamura, Tadashi
Hagiwara, Teruki
Ishizaka, Yukihito
Dohi, Taeko
Kawamura, Yuki I.
author_sort Otsubo, Takeshi
collection PubMed
description Long interspersed element-1 (L1) is a transposable element that can move within the genome, potentially leading to genome diversity and modified gene function. Although L1 activity in somatic cells is normally suppressed through DNA methylation, some L1s are activated in tumors including colorectal carcinoma. However, how L1-retrotransposition (L1-RTP) is involved in gastrointestinal disorders remains to be elucidated. We hypothesized that L1-RTP in somatic cells might contribute to colitis-associated cancer (CAC). To address this, we employed an experimental model of CAC using transgenic L1-reporter mice carrying a human L1-EGFP reporter gene. Mice were subjected to repeated cycles of colitis induced by administration of dextran sodium sulfate (DSS) in drinking water with injection of carcinogen azoxymethane (AOM). L1-RTP levels were measured by a quantitative polymerase chain reaction targeting the newly inserted reporter EGFP in various tissues and cell types, including samples obtained by laser microdissection and cell sorting with flow cytometry. DNA methylation levels of the human L1 promoter were analyzed by bisulfite pyrosequencing. AOM+DSS-treated mice exhibited significantly higher levels of L1-RTP in whole colon tissue during the acute phase of colitis when compared with control naïve mice. L1-RTP levels in whole colon tissue were positively correlated with the histological severity of colitis and degree of neutrophil infiltration into the lamina propria (LP), but not with tumor development in the colon. L1-RTP was enriched in LP mesenchymal cells rather than epithelial cells (ECs), myeloid, or lymphoid cells. DNA methylation levels of the human L1 promoter region showed a negative correlation with L1-RTP levels. L1-RTP was absent from most tumors found in 22-week-old mice. In conclusion, we demonstrated that L1-RTP was induced in the mouse CAC mucosa in accordance with the acute inflammatory response; however, retrotransposition appears not to have direct relevance to colitis-induced cancer initiation.
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spelling pubmed-43398392015-03-04 Retrotransposition of Long Interspersed Nucleotide Element-1 Is Associated with Colitis but Not Tumors in a Murine Colitic Cancer Model Otsubo, Takeshi Okamura, Tadashi Hagiwara, Teruki Ishizaka, Yukihito Dohi, Taeko Kawamura, Yuki I. PLoS One Research Article Long interspersed element-1 (L1) is a transposable element that can move within the genome, potentially leading to genome diversity and modified gene function. Although L1 activity in somatic cells is normally suppressed through DNA methylation, some L1s are activated in tumors including colorectal carcinoma. However, how L1-retrotransposition (L1-RTP) is involved in gastrointestinal disorders remains to be elucidated. We hypothesized that L1-RTP in somatic cells might contribute to colitis-associated cancer (CAC). To address this, we employed an experimental model of CAC using transgenic L1-reporter mice carrying a human L1-EGFP reporter gene. Mice were subjected to repeated cycles of colitis induced by administration of dextran sodium sulfate (DSS) in drinking water with injection of carcinogen azoxymethane (AOM). L1-RTP levels were measured by a quantitative polymerase chain reaction targeting the newly inserted reporter EGFP in various tissues and cell types, including samples obtained by laser microdissection and cell sorting with flow cytometry. DNA methylation levels of the human L1 promoter were analyzed by bisulfite pyrosequencing. AOM+DSS-treated mice exhibited significantly higher levels of L1-RTP in whole colon tissue during the acute phase of colitis when compared with control naïve mice. L1-RTP levels in whole colon tissue were positively correlated with the histological severity of colitis and degree of neutrophil infiltration into the lamina propria (LP), but not with tumor development in the colon. L1-RTP was enriched in LP mesenchymal cells rather than epithelial cells (ECs), myeloid, or lymphoid cells. DNA methylation levels of the human L1 promoter region showed a negative correlation with L1-RTP levels. L1-RTP was absent from most tumors found in 22-week-old mice. In conclusion, we demonstrated that L1-RTP was induced in the mouse CAC mucosa in accordance with the acute inflammatory response; however, retrotransposition appears not to have direct relevance to colitis-induced cancer initiation. Public Library of Science 2015-02-24 /pmc/articles/PMC4339839/ /pubmed/25710700 http://dx.doi.org/10.1371/journal.pone.0116072 Text en © 2015 Otsubo 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
Otsubo, Takeshi
Okamura, Tadashi
Hagiwara, Teruki
Ishizaka, Yukihito
Dohi, Taeko
Kawamura, Yuki I.
Retrotransposition of Long Interspersed Nucleotide Element-1 Is Associated with Colitis but Not Tumors in a Murine Colitic Cancer Model
title Retrotransposition of Long Interspersed Nucleotide Element-1 Is Associated with Colitis but Not Tumors in a Murine Colitic Cancer Model
title_full Retrotransposition of Long Interspersed Nucleotide Element-1 Is Associated with Colitis but Not Tumors in a Murine Colitic Cancer Model
title_fullStr Retrotransposition of Long Interspersed Nucleotide Element-1 Is Associated with Colitis but Not Tumors in a Murine Colitic Cancer Model
title_full_unstemmed Retrotransposition of Long Interspersed Nucleotide Element-1 Is Associated with Colitis but Not Tumors in a Murine Colitic Cancer Model
title_short Retrotransposition of Long Interspersed Nucleotide Element-1 Is Associated with Colitis but Not Tumors in a Murine Colitic Cancer Model
title_sort retrotransposition of long interspersed nucleotide element-1 is associated with colitis but not tumors in a murine colitic cancer model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339839/
https://www.ncbi.nlm.nih.gov/pubmed/25710700
http://dx.doi.org/10.1371/journal.pone.0116072
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