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SHMT1 inhibits the metastasis of HCC by repressing NOX1-mediated ROS production
BACKGROUND: Hepatocellular carcinoma (HCC) is the most major type of primary hepatic cancer. Serine hydroxymethyltransferase 1 (SHMT1) is recently found to play critical roles in human cancers including lung cancer, ovarian cancer and intestinal cancer. However, the expression, function and the unde...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373090/ https://www.ncbi.nlm.nih.gov/pubmed/30755243 http://dx.doi.org/10.1186/s13046-019-1067-5 |
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author | Dou, Changwei Xu, Qiuran Liu, Jie Wang, Yufeng Zhou, Zhenyu Yao, Weifeng Jiang, Kai Cheng, Jian Zhang, Chengwu Tu, Kangsheng |
author_facet | Dou, Changwei Xu, Qiuran Liu, Jie Wang, Yufeng Zhou, Zhenyu Yao, Weifeng Jiang, Kai Cheng, Jian Zhang, Chengwu Tu, Kangsheng |
author_sort | Dou, Changwei |
collection | PubMed |
description | BACKGROUND: Hepatocellular carcinoma (HCC) is the most major type of primary hepatic cancer. Serine hydroxymethyltransferase 1 (SHMT1) is recently found to play critical roles in human cancers including lung cancer, ovarian cancer and intestinal cancer. However, the expression, function and the underlying mechanisms of SHMT1 in HCC remain uncovered. METHODS: qRT-PCR, immunohistochemistry and immunoblotting were performed to detect the expression of SHMT1 in HCC tissues and cell lines. HCC cell migration and invasion were determined by Boyden chamber and Transwell assay in vitro, and tumor metastasis was assessed via lung metastasis model in mice. The expression of key factors involved in epithelial-to-mesenchymal transition (EMT) process was evaluated by western blotting. RESULTS: In this study, data mining of public databases and analysis of clinical specimens demonstrated that SHMT1 expression was decreased in HCC. Reduced SHMT1 level was correlated with unfavorable clinicopathological features and poor prognosis of HCC patients. Gain- and loss-of-function experiments showed that SHMT1 overexpression inhibited the migration and invasion of HCCLM3 cells while SHMT1 knockdown enhanced the metastatic ability of Hep3B cells. Furthermore, qRT-PCR and western blotting showed that SHMT1 inhibited EMT and matrix metallopeptidase 2 (MMP2) expression. In vivo experiments showed that SHMT1 suppressed the lung metastasis of HCC cells in mice. Mechanistically, SHMT1 knockdown enhanced reactive oxygen species (ROS) production, and thus promoted the motility, EMT and MMP2 expression in Hep3B cells. Furthermore, NADPH oxidase 1 (NOX1) was identified to be the downstream target of SHMT1 in HCC. NOX1 expression was negatively correlated with SHMT1 expression in HCC. Rescue experiments revealed that NOX1 mediated the functional influence of SHMT1 on HCC cells. CONCLUSIONS: These data indicate that SHMT1 inhibits the metastasis of HCC by repressing NOX1 mediated ROS production. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-019-1067-5) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6373090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-63730902019-02-25 SHMT1 inhibits the metastasis of HCC by repressing NOX1-mediated ROS production Dou, Changwei Xu, Qiuran Liu, Jie Wang, Yufeng Zhou, Zhenyu Yao, Weifeng Jiang, Kai Cheng, Jian Zhang, Chengwu Tu, Kangsheng J Exp Clin Cancer Res Research BACKGROUND: Hepatocellular carcinoma (HCC) is the most major type of primary hepatic cancer. Serine hydroxymethyltransferase 1 (SHMT1) is recently found to play critical roles in human cancers including lung cancer, ovarian cancer and intestinal cancer. However, the expression, function and the underlying mechanisms of SHMT1 in HCC remain uncovered. METHODS: qRT-PCR, immunohistochemistry and immunoblotting were performed to detect the expression of SHMT1 in HCC tissues and cell lines. HCC cell migration and invasion were determined by Boyden chamber and Transwell assay in vitro, and tumor metastasis was assessed via lung metastasis model in mice. The expression of key factors involved in epithelial-to-mesenchymal transition (EMT) process was evaluated by western blotting. RESULTS: In this study, data mining of public databases and analysis of clinical specimens demonstrated that SHMT1 expression was decreased in HCC. Reduced SHMT1 level was correlated with unfavorable clinicopathological features and poor prognosis of HCC patients. Gain- and loss-of-function experiments showed that SHMT1 overexpression inhibited the migration and invasion of HCCLM3 cells while SHMT1 knockdown enhanced the metastatic ability of Hep3B cells. Furthermore, qRT-PCR and western blotting showed that SHMT1 inhibited EMT and matrix metallopeptidase 2 (MMP2) expression. In vivo experiments showed that SHMT1 suppressed the lung metastasis of HCC cells in mice. Mechanistically, SHMT1 knockdown enhanced reactive oxygen species (ROS) production, and thus promoted the motility, EMT and MMP2 expression in Hep3B cells. Furthermore, NADPH oxidase 1 (NOX1) was identified to be the downstream target of SHMT1 in HCC. NOX1 expression was negatively correlated with SHMT1 expression in HCC. Rescue experiments revealed that NOX1 mediated the functional influence of SHMT1 on HCC cells. CONCLUSIONS: These data indicate that SHMT1 inhibits the metastasis of HCC by repressing NOX1 mediated ROS production. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-019-1067-5) contains supplementary material, which is available to authorized users. BioMed Central 2019-02-12 /pmc/articles/PMC6373090/ /pubmed/30755243 http://dx.doi.org/10.1186/s13046-019-1067-5 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 Dou, Changwei Xu, Qiuran Liu, Jie Wang, Yufeng Zhou, Zhenyu Yao, Weifeng Jiang, Kai Cheng, Jian Zhang, Chengwu Tu, Kangsheng SHMT1 inhibits the metastasis of HCC by repressing NOX1-mediated ROS production |
title | SHMT1 inhibits the metastasis of HCC by repressing NOX1-mediated ROS production |
title_full | SHMT1 inhibits the metastasis of HCC by repressing NOX1-mediated ROS production |
title_fullStr | SHMT1 inhibits the metastasis of HCC by repressing NOX1-mediated ROS production |
title_full_unstemmed | SHMT1 inhibits the metastasis of HCC by repressing NOX1-mediated ROS production |
title_short | SHMT1 inhibits the metastasis of HCC by repressing NOX1-mediated ROS production |
title_sort | shmt1 inhibits the metastasis of hcc by repressing nox1-mediated ros production |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373090/ https://www.ncbi.nlm.nih.gov/pubmed/30755243 http://dx.doi.org/10.1186/s13046-019-1067-5 |
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