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An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma

BACKGROUND: Aberrant activation of Notch signaling has been causally linked to the metastasis of hepatocellular carcinoma (HCC), however the underlying molecular mechanisms are still poorly understood. RING finger protein 187 (RNF187) was recently revealed to be a driver of several cancers, but its...

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Autores principales: Zhang, Lei, Chen, Jiewei, Yong, Juanjuan, Qiao, Liang, Xu, Leibo, Liu, Chao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720101/
https://www.ncbi.nlm.nih.gov/pubmed/31477177
http://dx.doi.org/10.1186/s13046-019-1382-x
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author Zhang, Lei
Chen, Jiewei
Yong, Juanjuan
Qiao, Liang
Xu, Leibo
Liu, Chao
author_facet Zhang, Lei
Chen, Jiewei
Yong, Juanjuan
Qiao, Liang
Xu, Leibo
Liu, Chao
author_sort Zhang, Lei
collection PubMed
description BACKGROUND: Aberrant activation of Notch signaling has been causally linked to the metastasis of hepatocellular carcinoma (HCC), however the underlying molecular mechanisms are still poorly understood. RING finger protein 187 (RNF187) was recently revealed to be a driver of several cancers, but its expression pattern and biological function in HCC are unknown. METHODS: The expression levels of Notch1 and RNF187 were assessed in two independent cohorts of HCC tissues, and modulation of Notch1 in HCC cells was performed to explore the regulatory role of Notch1 in HCC metastasis. RNA-sequencing (RNA-seq), bioinformatics analysis, luciferase reporter analysis, and chromatin immunoprecipitation assay (ChIP) were used to clarify the relationship between Notch1 signaling and its potential target Ring finger protein 187 (RNF187). Gain- and loss-of-function studies were used to dissect the role of Notch1-RNF187 signaling in promoting HCC metastasis. The impact of Notch1-RNF187 activity in determining clinical prognosis for HCC patients was evaluated by multivariate Cox regression. RESULTS: By RNA-seq, luciferase reporter analysis, and ChIP assay, RNF187 was confirmed to be a direct transcriptional target of Notch1, as Notch1 could activate RNF187 promoter whereas the pro-migratory and pro-invasive effects of Notch1 were significantly attenuated by RNF187 knockdown. Meanwhile, RNF187 silencing could attenuate the Notch1-dependent epithelial-mesenchymal transition (EMT). Moreover, overexpression of RNF187 counteracted the inhibitory effect of Notch1 knockdown on cancer progression. Importantly, HCC patients with high level of hepatic Notch1 expression had shorter disease-free survival (DFS) than those with low level of hepatic Notch1 expression. Furthermore, patients with high level of Notch1 and RNF187 co-expression showed the shortest DFS. The expression level of Notch1 and RNF187 was an independent prognostic factor for HCC. CONCLUSIONS: For the first time we identified that RNF187 is an essential factor for Notch1 to promote invasion and metastasis of HCC. Of highly clinical relevance, we found that activation of Notch1-RNF187 correlates with a worse prognosis of HCC patients. These findings provide a solid foundation for developing novel strategies to tackle HCC metastasis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-019-1382-x) contains supplementary material, which is available to authorized users.
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spelling pubmed-67201012019-09-06 An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma Zhang, Lei Chen, Jiewei Yong, Juanjuan Qiao, Liang Xu, Leibo Liu, Chao J Exp Clin Cancer Res Research BACKGROUND: Aberrant activation of Notch signaling has been causally linked to the metastasis of hepatocellular carcinoma (HCC), however the underlying molecular mechanisms are still poorly understood. RING finger protein 187 (RNF187) was recently revealed to be a driver of several cancers, but its expression pattern and biological function in HCC are unknown. METHODS: The expression levels of Notch1 and RNF187 were assessed in two independent cohorts of HCC tissues, and modulation of Notch1 in HCC cells was performed to explore the regulatory role of Notch1 in HCC metastasis. RNA-sequencing (RNA-seq), bioinformatics analysis, luciferase reporter analysis, and chromatin immunoprecipitation assay (ChIP) were used to clarify the relationship between Notch1 signaling and its potential target Ring finger protein 187 (RNF187). Gain- and loss-of-function studies were used to dissect the role of Notch1-RNF187 signaling in promoting HCC metastasis. The impact of Notch1-RNF187 activity in determining clinical prognosis for HCC patients was evaluated by multivariate Cox regression. RESULTS: By RNA-seq, luciferase reporter analysis, and ChIP assay, RNF187 was confirmed to be a direct transcriptional target of Notch1, as Notch1 could activate RNF187 promoter whereas the pro-migratory and pro-invasive effects of Notch1 were significantly attenuated by RNF187 knockdown. Meanwhile, RNF187 silencing could attenuate the Notch1-dependent epithelial-mesenchymal transition (EMT). Moreover, overexpression of RNF187 counteracted the inhibitory effect of Notch1 knockdown on cancer progression. Importantly, HCC patients with high level of hepatic Notch1 expression had shorter disease-free survival (DFS) than those with low level of hepatic Notch1 expression. Furthermore, patients with high level of Notch1 and RNF187 co-expression showed the shortest DFS. The expression level of Notch1 and RNF187 was an independent prognostic factor for HCC. CONCLUSIONS: For the first time we identified that RNF187 is an essential factor for Notch1 to promote invasion and metastasis of HCC. Of highly clinical relevance, we found that activation of Notch1-RNF187 correlates with a worse prognosis of HCC patients. These findings provide a solid foundation for developing novel strategies to tackle HCC metastasis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-019-1382-x) contains supplementary material, which is available to authorized users. BioMed Central 2019-09-02 /pmc/articles/PMC6720101/ /pubmed/31477177 http://dx.doi.org/10.1186/s13046-019-1382-x Text en © The Author(s). 2019 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
Zhang, Lei
Chen, Jiewei
Yong, Juanjuan
Qiao, Liang
Xu, Leibo
Liu, Chao
An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma
title An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma
title_full An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma
title_fullStr An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma
title_full_unstemmed An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma
title_short An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma
title_sort essential role of rnf187 in notch1 mediated metastasis of hepatocellular carcinoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720101/
https://www.ncbi.nlm.nih.gov/pubmed/31477177
http://dx.doi.org/10.1186/s13046-019-1382-x
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