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CtIP suppresses primary microRNA maturation and promotes metastasis of colon cancer cells in a xenograft mouse model

miRNAs are important regulators of eukaryotic gene expression. The post-transcriptional maturation of miRNAs is controlled by the Drosha-DiGeorge syndrome critical region gene 8 (DGCR8) microprocessor. Dysregulation of miRNA biogenesis has been implicated in the pathogenesis of human diseases, inclu...

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Autores principales: Ren, Jianping, Wu, Yan, Wang, Ya, Zhao, Yuqin, Li, Youhang, Hao, Shuailin, Lin, Lixiu, Zhang, Shuyuan, Xu, Xingzhi, Wang, Hailong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164041/
https://www.ncbi.nlm.nih.gov/pubmed/33901493
http://dx.doi.org/10.1016/j.jbc.2021.100707
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author Ren, Jianping
Wu, Yan
Wang, Ya
Zhao, Yuqin
Li, Youhang
Hao, Shuailin
Lin, Lixiu
Zhang, Shuyuan
Xu, Xingzhi
Wang, Hailong
author_facet Ren, Jianping
Wu, Yan
Wang, Ya
Zhao, Yuqin
Li, Youhang
Hao, Shuailin
Lin, Lixiu
Zhang, Shuyuan
Xu, Xingzhi
Wang, Hailong
author_sort Ren, Jianping
collection PubMed
description miRNAs are important regulators of eukaryotic gene expression. The post-transcriptional maturation of miRNAs is controlled by the Drosha-DiGeorge syndrome critical region gene 8 (DGCR8) microprocessor. Dysregulation of miRNA biogenesis has been implicated in the pathogenesis of human diseases, including cancers. C-terminal–binding protein–interacting protein (CtIP) is a well-known DNA repair factor that promotes the processing of DNA double-strand break (DSB) to initiate homologous recombination–mediated DSB repair. However, it was unclear whether CtIP has other unknown cellular functions. Here, we aimed to uncover the roles of CtIP in miRNA maturation and cancer cell metastasis. We found that CtIP is a potential regulatory factor that suppresses the processing of miRNA primary transcripts (pri-miRNA). CtIP directly bound to both DGCR8 and pri-miRNAs through a conserved Sae2-like domain, reduced the binding of Drosha to DGCR8 and pri-miRNA substrate, and inhibited processing activity of Drosha complex. CtIP depletion significantly increased the expression levels of a subset of mature miRNAs, including miR-302 family members that are associated with tumor progression and metastasis in several cancer types. We also found that CtIP-inhibited miRNAs, such as miR-302 family members, are not crucial for DSB repair. However, increase of miR-302b levels or loss of CtIP function severely suppressed human colon cancer cell line tumor cell metastasis in a mouse xenograft model. These studies reveal a previously unrecognized mechanism of CtIP in miRNA processing and tumor metastasis that represents a new function of CtIP in cancer.
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spelling pubmed-81640412021-06-04 CtIP suppresses primary microRNA maturation and promotes metastasis of colon cancer cells in a xenograft mouse model Ren, Jianping Wu, Yan Wang, Ya Zhao, Yuqin Li, Youhang Hao, Shuailin Lin, Lixiu Zhang, Shuyuan Xu, Xingzhi Wang, Hailong J Biol Chem Research Article miRNAs are important regulators of eukaryotic gene expression. The post-transcriptional maturation of miRNAs is controlled by the Drosha-DiGeorge syndrome critical region gene 8 (DGCR8) microprocessor. Dysregulation of miRNA biogenesis has been implicated in the pathogenesis of human diseases, including cancers. C-terminal–binding protein–interacting protein (CtIP) is a well-known DNA repair factor that promotes the processing of DNA double-strand break (DSB) to initiate homologous recombination–mediated DSB repair. However, it was unclear whether CtIP has other unknown cellular functions. Here, we aimed to uncover the roles of CtIP in miRNA maturation and cancer cell metastasis. We found that CtIP is a potential regulatory factor that suppresses the processing of miRNA primary transcripts (pri-miRNA). CtIP directly bound to both DGCR8 and pri-miRNAs through a conserved Sae2-like domain, reduced the binding of Drosha to DGCR8 and pri-miRNA substrate, and inhibited processing activity of Drosha complex. CtIP depletion significantly increased the expression levels of a subset of mature miRNAs, including miR-302 family members that are associated with tumor progression and metastasis in several cancer types. We also found that CtIP-inhibited miRNAs, such as miR-302 family members, are not crucial for DSB repair. However, increase of miR-302b levels or loss of CtIP function severely suppressed human colon cancer cell line tumor cell metastasis in a mouse xenograft model. These studies reveal a previously unrecognized mechanism of CtIP in miRNA processing and tumor metastasis that represents a new function of CtIP in cancer. American Society for Biochemistry and Molecular Biology 2021-04-24 /pmc/articles/PMC8164041/ /pubmed/33901493 http://dx.doi.org/10.1016/j.jbc.2021.100707 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Ren, Jianping
Wu, Yan
Wang, Ya
Zhao, Yuqin
Li, Youhang
Hao, Shuailin
Lin, Lixiu
Zhang, Shuyuan
Xu, Xingzhi
Wang, Hailong
CtIP suppresses primary microRNA maturation and promotes metastasis of colon cancer cells in a xenograft mouse model
title CtIP suppresses primary microRNA maturation and promotes metastasis of colon cancer cells in a xenograft mouse model
title_full CtIP suppresses primary microRNA maturation and promotes metastasis of colon cancer cells in a xenograft mouse model
title_fullStr CtIP suppresses primary microRNA maturation and promotes metastasis of colon cancer cells in a xenograft mouse model
title_full_unstemmed CtIP suppresses primary microRNA maturation and promotes metastasis of colon cancer cells in a xenograft mouse model
title_short CtIP suppresses primary microRNA maturation and promotes metastasis of colon cancer cells in a xenograft mouse model
title_sort ctip suppresses primary microrna maturation and promotes metastasis of colon cancer cells in a xenograft mouse model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164041/
https://www.ncbi.nlm.nih.gov/pubmed/33901493
http://dx.doi.org/10.1016/j.jbc.2021.100707
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