Cargando…
miR-155, identified as anti-metastatic by global miRNA profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations
To gain insight into miRNA regulation in metastasis formation, we used a metastasis cell line model that allows investigation of extravasation and colonization of circulating cancer cells to lungs in mice. Using global miRNA profiling, 28 miRNAs were found to exhibit significantly altered expression...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745722/ https://www.ncbi.nlm.nih.gov/pubmed/26317550 |
_version_ | 1782414703579889664 |
---|---|
author | Thomsen, Karina G. Terp, Mikkel G. Lund, Rikke R. Søkilde, Rolf Elias, Daniel Bak, Martin Litman, Thomas Beck, Hans C. Lyng, Maria B. Ditzel, Henrik J. |
author_facet | Thomsen, Karina G. Terp, Mikkel G. Lund, Rikke R. Søkilde, Rolf Elias, Daniel Bak, Martin Litman, Thomas Beck, Hans C. Lyng, Maria B. Ditzel, Henrik J. |
author_sort | Thomsen, Karina G. |
collection | PubMed |
description | To gain insight into miRNA regulation in metastasis formation, we used a metastasis cell line model that allows investigation of extravasation and colonization of circulating cancer cells to lungs in mice. Using global miRNA profiling, 28 miRNAs were found to exhibit significantly altered expression between isogenic metastasizing and non-metastasizing cancer cells, with miR-155 being the most differentially expressed. Highly metastatic mesenchymal-like CL16 cancer cells showed very low miR-155 expression, and miR-155 overexpression in these cells lead to significantly decreased tumor burden in lungs when injected intravenously in immunodeficient mice. Our experiments addressing the underlying mechanism of the altered tumor burden revealed that miR-155-overexpressing CL16 cells were less invasive than CL16 control cells in vitro, while miR-155 overexpression had no effect on cancer cell proliferation or apoptosis in established lung tumors. To identify proteins regulated by miR-155 and thus delineate its function in our cell model, we compared the proteome of xenograft tumors derived from miR-155-overexpressing CL16 cells and CL16 control cells using mass spectrometry-based proteomics. >4,000 proteins were identified, of which 92 were consistently differentially expressed. Network analysis revealed that the altered proteins were associated with cellular functions such as movement, growth and survival as well as cell-to-cell signaling and interaction. Downregulation of the three metastasis-associated proteins ALDH1A1, PIR and PDCD4 in miR-155-overexpressing tumors was validated by immunohistochemistry. Our results demonstrate that miR-155 inhibits the ability of cancer cells to extravasate and/or colonize at distant organs and brings additional insight into the complexity of miR-155 regulation in metastatic seeding. |
format | Online Article Text |
id | pubmed-4745722 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-47457222016-02-23 miR-155, identified as anti-metastatic by global miRNA profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations Thomsen, Karina G. Terp, Mikkel G. Lund, Rikke R. Søkilde, Rolf Elias, Daniel Bak, Martin Litman, Thomas Beck, Hans C. Lyng, Maria B. Ditzel, Henrik J. Oncotarget Research Paper To gain insight into miRNA regulation in metastasis formation, we used a metastasis cell line model that allows investigation of extravasation and colonization of circulating cancer cells to lungs in mice. Using global miRNA profiling, 28 miRNAs were found to exhibit significantly altered expression between isogenic metastasizing and non-metastasizing cancer cells, with miR-155 being the most differentially expressed. Highly metastatic mesenchymal-like CL16 cancer cells showed very low miR-155 expression, and miR-155 overexpression in these cells lead to significantly decreased tumor burden in lungs when injected intravenously in immunodeficient mice. Our experiments addressing the underlying mechanism of the altered tumor burden revealed that miR-155-overexpressing CL16 cells were less invasive than CL16 control cells in vitro, while miR-155 overexpression had no effect on cancer cell proliferation or apoptosis in established lung tumors. To identify proteins regulated by miR-155 and thus delineate its function in our cell model, we compared the proteome of xenograft tumors derived from miR-155-overexpressing CL16 cells and CL16 control cells using mass spectrometry-based proteomics. >4,000 proteins were identified, of which 92 were consistently differentially expressed. Network analysis revealed that the altered proteins were associated with cellular functions such as movement, growth and survival as well as cell-to-cell signaling and interaction. Downregulation of the three metastasis-associated proteins ALDH1A1, PIR and PDCD4 in miR-155-overexpressing tumors was validated by immunohistochemistry. Our results demonstrate that miR-155 inhibits the ability of cancer cells to extravasate and/or colonize at distant organs and brings additional insight into the complexity of miR-155 regulation in metastatic seeding. Impact Journals LLC 2015-08-10 /pmc/articles/PMC4745722/ /pubmed/26317550 Text en Copyright: © 2015 Thomsen et al. http://creativecommons.org/licenses/by/2.5/ 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 credited. |
spellingShingle | Research Paper Thomsen, Karina G. Terp, Mikkel G. Lund, Rikke R. Søkilde, Rolf Elias, Daniel Bak, Martin Litman, Thomas Beck, Hans C. Lyng, Maria B. Ditzel, Henrik J. miR-155, identified as anti-metastatic by global miRNA profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations |
title | miR-155, identified as anti-metastatic by global miRNA profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations |
title_full | miR-155, identified as anti-metastatic by global miRNA profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations |
title_fullStr | miR-155, identified as anti-metastatic by global miRNA profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations |
title_full_unstemmed | miR-155, identified as anti-metastatic by global miRNA profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations |
title_short | miR-155, identified as anti-metastatic by global miRNA profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations |
title_sort | mir-155, identified as anti-metastatic by global mirna profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745722/ https://www.ncbi.nlm.nih.gov/pubmed/26317550 |
work_keys_str_mv | AT thomsenkarinag mir155identifiedasantimetastaticbyglobalmirnaprofilingofametastasismodelinhibitscancercellextravasationandcolonizationinvivoandcausessignificantsignalingalterations AT terpmikkelg mir155identifiedasantimetastaticbyglobalmirnaprofilingofametastasismodelinhibitscancercellextravasationandcolonizationinvivoandcausessignificantsignalingalterations AT lundrikker mir155identifiedasantimetastaticbyglobalmirnaprofilingofametastasismodelinhibitscancercellextravasationandcolonizationinvivoandcausessignificantsignalingalterations AT søkilderolf mir155identifiedasantimetastaticbyglobalmirnaprofilingofametastasismodelinhibitscancercellextravasationandcolonizationinvivoandcausessignificantsignalingalterations AT eliasdaniel mir155identifiedasantimetastaticbyglobalmirnaprofilingofametastasismodelinhibitscancercellextravasationandcolonizationinvivoandcausessignificantsignalingalterations AT bakmartin mir155identifiedasantimetastaticbyglobalmirnaprofilingofametastasismodelinhibitscancercellextravasationandcolonizationinvivoandcausessignificantsignalingalterations AT litmanthomas mir155identifiedasantimetastaticbyglobalmirnaprofilingofametastasismodelinhibitscancercellextravasationandcolonizationinvivoandcausessignificantsignalingalterations AT beckhansc mir155identifiedasantimetastaticbyglobalmirnaprofilingofametastasismodelinhibitscancercellextravasationandcolonizationinvivoandcausessignificantsignalingalterations AT lyngmariab mir155identifiedasantimetastaticbyglobalmirnaprofilingofametastasismodelinhibitscancercellextravasationandcolonizationinvivoandcausessignificantsignalingalterations AT ditzelhenrikj mir155identifiedasantimetastaticbyglobalmirnaprofilingofametastasismodelinhibitscancercellextravasationandcolonizationinvivoandcausessignificantsignalingalterations |