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Capicua suppresses colorectal cancer progression via repression of ETV4 expression

BACKGROUND: Although major driver gene mutations have been identified, the complex molecular heterogeneity of colorectal cancer (CRC) remains unclear. Capicua (CIC) functions as a tumor suppressor in various types of cancers; however, its role in CRC progression has not been examined. METHODS: Datab...

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Autores principales: Lee, Jeon-Soo, Kim, Eunjeong, Lee, Jongeun, Kim, Donghyo, Kim, Hyeongjoo, Kim, Chang-Jin, Kim, Sanguk, Jeong, Dongjun, Lee, Yoontae
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003492/
https://www.ncbi.nlm.nih.gov/pubmed/32042269
http://dx.doi.org/10.1186/s12935-020-1111-8
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author Lee, Jeon-Soo
Kim, Eunjeong
Lee, Jongeun
Kim, Donghyo
Kim, Hyeongjoo
Kim, Chang-Jin
Kim, Sanguk
Jeong, Dongjun
Lee, Yoontae
author_facet Lee, Jeon-Soo
Kim, Eunjeong
Lee, Jongeun
Kim, Donghyo
Kim, Hyeongjoo
Kim, Chang-Jin
Kim, Sanguk
Jeong, Dongjun
Lee, Yoontae
author_sort Lee, Jeon-Soo
collection PubMed
description BACKGROUND: Although major driver gene mutations have been identified, the complex molecular heterogeneity of colorectal cancer (CRC) remains unclear. Capicua (CIC) functions as a tumor suppressor in various types of cancers; however, its role in CRC progression has not been examined. METHODS: Databases for gene expression profile in CRC patient samples were used to evaluate the association of the levels of CIC and Polyoma enhancer activator 3 (PEA3) group genes (ETS translocation variant 1 (ETV1), ETV4, and ETV5), the best-characterized CIC targets in terms of CIC functions, with clinicopathological features of CRC. CIC and ETV4 protein levels were also examined in CRC patient tissue samples. Gain- and loss-of function experiments in cell lines and mouse xenograft models were performed to investigate regulatory functions of CIC and ETV4 in CRC cell growth and invasion. qRT-PCR and western blot analyses were performed to verify the CIC regulation of ETV4 expression in CRC cells. Rescue experiments were conducted using siRNA against ETV4 and CIC-deficient CRC cell lines. RESULTS: CIC expression was decreased in the tissue samples of CRC patients. Cell invasion, migration, and proliferation were enhanced in CIC-deficient CRC cells and suppressed in CIC-overexpressing cells. Among PEA3 group genes, ETV4 levels were most dramatically upregulated and inversely correlated with the CIC levels in CRC patient samples. Furthermore, derepression of ETV4 was more prominent in CIC-deficient CRC cells, when compared with that observed for ETV1 and ETV5. The enhanced cell proliferative and invasive capabilities in CIC-deficient CRC cells were completely recovered by knockdown of ETV4. CONCLUSION: Collectively, the CIC-ETV4 axis is not only a key module that controls CRC progression but also a novel therapeutic and/or diagnostic target for CRC.
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spelling pubmed-70034922020-02-10 Capicua suppresses colorectal cancer progression via repression of ETV4 expression Lee, Jeon-Soo Kim, Eunjeong Lee, Jongeun Kim, Donghyo Kim, Hyeongjoo Kim, Chang-Jin Kim, Sanguk Jeong, Dongjun Lee, Yoontae Cancer Cell Int Primary Research BACKGROUND: Although major driver gene mutations have been identified, the complex molecular heterogeneity of colorectal cancer (CRC) remains unclear. Capicua (CIC) functions as a tumor suppressor in various types of cancers; however, its role in CRC progression has not been examined. METHODS: Databases for gene expression profile in CRC patient samples were used to evaluate the association of the levels of CIC and Polyoma enhancer activator 3 (PEA3) group genes (ETS translocation variant 1 (ETV1), ETV4, and ETV5), the best-characterized CIC targets in terms of CIC functions, with clinicopathological features of CRC. CIC and ETV4 protein levels were also examined in CRC patient tissue samples. Gain- and loss-of function experiments in cell lines and mouse xenograft models were performed to investigate regulatory functions of CIC and ETV4 in CRC cell growth and invasion. qRT-PCR and western blot analyses were performed to verify the CIC regulation of ETV4 expression in CRC cells. Rescue experiments were conducted using siRNA against ETV4 and CIC-deficient CRC cell lines. RESULTS: CIC expression was decreased in the tissue samples of CRC patients. Cell invasion, migration, and proliferation were enhanced in CIC-deficient CRC cells and suppressed in CIC-overexpressing cells. Among PEA3 group genes, ETV4 levels were most dramatically upregulated and inversely correlated with the CIC levels in CRC patient samples. Furthermore, derepression of ETV4 was more prominent in CIC-deficient CRC cells, when compared with that observed for ETV1 and ETV5. The enhanced cell proliferative and invasive capabilities in CIC-deficient CRC cells were completely recovered by knockdown of ETV4. CONCLUSION: Collectively, the CIC-ETV4 axis is not only a key module that controls CRC progression but also a novel therapeutic and/or diagnostic target for CRC. BioMed Central 2020-02-05 /pmc/articles/PMC7003492/ /pubmed/32042269 http://dx.doi.org/10.1186/s12935-020-1111-8 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Primary Research
Lee, Jeon-Soo
Kim, Eunjeong
Lee, Jongeun
Kim, Donghyo
Kim, Hyeongjoo
Kim, Chang-Jin
Kim, Sanguk
Jeong, Dongjun
Lee, Yoontae
Capicua suppresses colorectal cancer progression via repression of ETV4 expression
title Capicua suppresses colorectal cancer progression via repression of ETV4 expression
title_full Capicua suppresses colorectal cancer progression via repression of ETV4 expression
title_fullStr Capicua suppresses colorectal cancer progression via repression of ETV4 expression
title_full_unstemmed Capicua suppresses colorectal cancer progression via repression of ETV4 expression
title_short Capicua suppresses colorectal cancer progression via repression of ETV4 expression
title_sort capicua suppresses colorectal cancer progression via repression of etv4 expression
topic Primary Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003492/
https://www.ncbi.nlm.nih.gov/pubmed/32042269
http://dx.doi.org/10.1186/s12935-020-1111-8
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