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Up-regulated NRIP2 in colorectal cancer initiating cells modulates the Wnt pathway by targeting RORβ

BACKGROUND: Colorectal cancer remains one of the most common malignant tumors worldwide. Colorectal cancer initiating cells (CCICs) are a small subpopulation responsible for malignant behaviors of colorectal cancer. Aberrant activation of the Wnt pathways regulates the self-renewal of CCIC. However,...

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Autores principales: Wen, Zhenzhen, Pan, Tianhui, Yang, Saisai, Liu, Jingwen, Tao, Haiying, Zhao, Yiming, Xu, Dingting, Shao, Wei, Wu, Jia, Liu, Xiyong, Wang, Yongjiang, Mao, Jianshan, Zhu, Yongliang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282884/
https://www.ncbi.nlm.nih.gov/pubmed/28137278
http://dx.doi.org/10.1186/s12943-017-0590-2
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author Wen, Zhenzhen
Pan, Tianhui
Yang, Saisai
Liu, Jingwen
Tao, Haiying
Zhao, Yiming
Xu, Dingting
Shao, Wei
Wu, Jia
Liu, Xiyong
Wang, Yongjiang
Mao, Jianshan
Zhu, Yongliang
author_facet Wen, Zhenzhen
Pan, Tianhui
Yang, Saisai
Liu, Jingwen
Tao, Haiying
Zhao, Yiming
Xu, Dingting
Shao, Wei
Wu, Jia
Liu, Xiyong
Wang, Yongjiang
Mao, Jianshan
Zhu, Yongliang
author_sort Wen, Zhenzhen
collection PubMed
description BACKGROUND: Colorectal cancer remains one of the most common malignant tumors worldwide. Colorectal cancer initiating cells (CCICs) are a small subpopulation responsible for malignant behaviors of colorectal cancer. Aberrant activation of the Wnt pathways regulates the self-renewal of CCIC. However, the underlying mechanism(s) remain poorly understood. METHODS: Via retroviral library screening, we identified Nuclear Receptor-Interacting Protein 2 (NRIP2) as a novel interactor of the Wnt pathway from enriched colorectal cancer colosphere cells. The expression levels of NRIP2 and retinoic acid-related orphan receptor β (RORβ) were further examined by FISH, qRT-PCR, IHC and Western blot. NRIP2 overexpressed and knockdown colorectal cancer cells were produced to study the role of NRIP2 in Wnt pathway. We also verified the binding between NRIP2 and RORβ and investigated the effect of RORβ on CCICs both in vitro and in vivo. Genechip-scanning speculated downstream target HBP1. Western blot, ChIP and luciferase reporter were carried to investigate the interaction between NRIP2, RORβ, and HBP1. RESULTS: NRIP2 was significantly up-regulated in CCICs from both cell lines and primary colorectal cancer tissues. Reinforced expression of NRIP2 increased Wnt activity, while silencing of NRIP2 attenuated Wnt activity. The transcription factor RORβ was a key target through which NRIP2 regulated Wnt pathway activity. RORβ was a transcriptional enhancer of inhibitor HBP1 of the Wnt pathway. NRIP2 prevented RORβ to bind with downstream HBP1 promoter regions and reduced the transcription of HBP1. This, in turn, attenuated the HBP1-dependent inhibition of TCF4-mediated transcription. CONCLUSIONS: NRIP2 is a novel interactor of the Wnt pathway in colorectal cancer initiating cells. interactions between NRIP2, RORβ, and HBP1 mediate a new mechanism for CCIC self-renewal via the Wnt activity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-017-0590-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-52828842017-02-03 Up-regulated NRIP2 in colorectal cancer initiating cells modulates the Wnt pathway by targeting RORβ Wen, Zhenzhen Pan, Tianhui Yang, Saisai Liu, Jingwen Tao, Haiying Zhao, Yiming Xu, Dingting Shao, Wei Wu, Jia Liu, Xiyong Wang, Yongjiang Mao, Jianshan Zhu, Yongliang Mol Cancer Research BACKGROUND: Colorectal cancer remains one of the most common malignant tumors worldwide. Colorectal cancer initiating cells (CCICs) are a small subpopulation responsible for malignant behaviors of colorectal cancer. Aberrant activation of the Wnt pathways regulates the self-renewal of CCIC. However, the underlying mechanism(s) remain poorly understood. METHODS: Via retroviral library screening, we identified Nuclear Receptor-Interacting Protein 2 (NRIP2) as a novel interactor of the Wnt pathway from enriched colorectal cancer colosphere cells. The expression levels of NRIP2 and retinoic acid-related orphan receptor β (RORβ) were further examined by FISH, qRT-PCR, IHC and Western blot. NRIP2 overexpressed and knockdown colorectal cancer cells were produced to study the role of NRIP2 in Wnt pathway. We also verified the binding between NRIP2 and RORβ and investigated the effect of RORβ on CCICs both in vitro and in vivo. Genechip-scanning speculated downstream target HBP1. Western blot, ChIP and luciferase reporter were carried to investigate the interaction between NRIP2, RORβ, and HBP1. RESULTS: NRIP2 was significantly up-regulated in CCICs from both cell lines and primary colorectal cancer tissues. Reinforced expression of NRIP2 increased Wnt activity, while silencing of NRIP2 attenuated Wnt activity. The transcription factor RORβ was a key target through which NRIP2 regulated Wnt pathway activity. RORβ was a transcriptional enhancer of inhibitor HBP1 of the Wnt pathway. NRIP2 prevented RORβ to bind with downstream HBP1 promoter regions and reduced the transcription of HBP1. This, in turn, attenuated the HBP1-dependent inhibition of TCF4-mediated transcription. CONCLUSIONS: NRIP2 is a novel interactor of the Wnt pathway in colorectal cancer initiating cells. interactions between NRIP2, RORβ, and HBP1 mediate a new mechanism for CCIC self-renewal via the Wnt activity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-017-0590-2) contains supplementary material, which is available to authorized users. BioMed Central 2017-01-31 /pmc/articles/PMC5282884/ /pubmed/28137278 http://dx.doi.org/10.1186/s12943-017-0590-2 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.
spellingShingle Research
Wen, Zhenzhen
Pan, Tianhui
Yang, Saisai
Liu, Jingwen
Tao, Haiying
Zhao, Yiming
Xu, Dingting
Shao, Wei
Wu, Jia
Liu, Xiyong
Wang, Yongjiang
Mao, Jianshan
Zhu, Yongliang
Up-regulated NRIP2 in colorectal cancer initiating cells modulates the Wnt pathway by targeting RORβ
title Up-regulated NRIP2 in colorectal cancer initiating cells modulates the Wnt pathway by targeting RORβ
title_full Up-regulated NRIP2 in colorectal cancer initiating cells modulates the Wnt pathway by targeting RORβ
title_fullStr Up-regulated NRIP2 in colorectal cancer initiating cells modulates the Wnt pathway by targeting RORβ
title_full_unstemmed Up-regulated NRIP2 in colorectal cancer initiating cells modulates the Wnt pathway by targeting RORβ
title_short Up-regulated NRIP2 in colorectal cancer initiating cells modulates the Wnt pathway by targeting RORβ
title_sort up-regulated nrip2 in colorectal cancer initiating cells modulates the wnt pathway by targeting rorβ
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282884/
https://www.ncbi.nlm.nih.gov/pubmed/28137278
http://dx.doi.org/10.1186/s12943-017-0590-2
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