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NOD-like receptor X1 functions as a tumor suppressor by inhibiting epithelial-mesenchymal transition and inducing aging in hepatocellular carcinoma cells
BACKGROUND: This study was performed to investigate the role of nucleotide-binding oligomerization domain (NOD)-like receptor X1 (NLRX1) in regulating hepatocellular carcinoma (HCC) progression. METHODS: Expression levels of NLRX1 in clinical specimens and cell lines were determined by reverse trans...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828065/ https://www.ncbi.nlm.nih.gov/pubmed/29482578 http://dx.doi.org/10.1186/s13045-018-0573-9 |
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author | Hu, Bo Ding, Guang-Yu Fu, Pei-Yao Zhu, Xiao-Dong Ji, Yuan Shi, Guo-Ming Shen, Ying-Hao Cai, Jia-Bin Yang, Zhen Zhou, Jian Fan, Jia Sun, Hui-Chuan Kuang, Ming Huang, Cheng |
author_facet | Hu, Bo Ding, Guang-Yu Fu, Pei-Yao Zhu, Xiao-Dong Ji, Yuan Shi, Guo-Ming Shen, Ying-Hao Cai, Jia-Bin Yang, Zhen Zhou, Jian Fan, Jia Sun, Hui-Chuan Kuang, Ming Huang, Cheng |
author_sort | Hu, Bo |
collection | PubMed |
description | BACKGROUND: This study was performed to investigate the role of nucleotide-binding oligomerization domain (NOD)-like receptor X1 (NLRX1) in regulating hepatocellular carcinoma (HCC) progression. METHODS: Expression levels of NLRX1 in clinical specimens and cell lines were determined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot (WB). Transwell assays were conducted to evaluate the effect of NLRX1 on cell invasion, and flow cytometry was used to assess apoptosis. Expression patterns of key molecules in the phosphoinositide 3-kinase (PI3K)-AKT pathways were determined via WB. The effect of NLRX1 on cell senescence was evaluated with β-galactosidase assays. Kaplan-Meier analyses and Cox regression models were used for prognostic evaluation. RESULTS: NLRX1 was downregulated in tumor tissue compared with adjacent normal liver tissue. Low tumor NLRX1 expression was identified as an independent indicator for HCC prognosis (recurrence: hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.26–2.76, overall survival [OS] 2.26, 95% CI 1.44–3.56). NLRX1 over-expression (OE) significantly inhibited invasiveness ability and induced apoptosis in HCC cells. In vivo experiments showed that NLRX1 knock-down (KD) significantly promoted HCC growth. Mechanistically, NLRX1 exhibited a suppressor function by decreasing phosphorylation of AKT and thus downregulating Snail1 expression, which inhibited epithelial-mesenchymal-transition (EMT) in HCC cells. Moreover, NLRX1 OE could induce cell senescence via an AKT-P21-dependent manner. CONCLUSIONS: NLRX1 acted as a tumor suppressor in HCC by inducing apoptosis, promoting senescence, and decreasing invasiveness by repressing PI3K-AKT signaling pathway. Future investigations will focus on restoring expression of NLRX1 to provide new insights into HCC treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13045-018-0573-9) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5828065 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-58280652018-02-28 NOD-like receptor X1 functions as a tumor suppressor by inhibiting epithelial-mesenchymal transition and inducing aging in hepatocellular carcinoma cells Hu, Bo Ding, Guang-Yu Fu, Pei-Yao Zhu, Xiao-Dong Ji, Yuan Shi, Guo-Ming Shen, Ying-Hao Cai, Jia-Bin Yang, Zhen Zhou, Jian Fan, Jia Sun, Hui-Chuan Kuang, Ming Huang, Cheng J Hematol Oncol Research BACKGROUND: This study was performed to investigate the role of nucleotide-binding oligomerization domain (NOD)-like receptor X1 (NLRX1) in regulating hepatocellular carcinoma (HCC) progression. METHODS: Expression levels of NLRX1 in clinical specimens and cell lines were determined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot (WB). Transwell assays were conducted to evaluate the effect of NLRX1 on cell invasion, and flow cytometry was used to assess apoptosis. Expression patterns of key molecules in the phosphoinositide 3-kinase (PI3K)-AKT pathways were determined via WB. The effect of NLRX1 on cell senescence was evaluated with β-galactosidase assays. Kaplan-Meier analyses and Cox regression models were used for prognostic evaluation. RESULTS: NLRX1 was downregulated in tumor tissue compared with adjacent normal liver tissue. Low tumor NLRX1 expression was identified as an independent indicator for HCC prognosis (recurrence: hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.26–2.76, overall survival [OS] 2.26, 95% CI 1.44–3.56). NLRX1 over-expression (OE) significantly inhibited invasiveness ability and induced apoptosis in HCC cells. In vivo experiments showed that NLRX1 knock-down (KD) significantly promoted HCC growth. Mechanistically, NLRX1 exhibited a suppressor function by decreasing phosphorylation of AKT and thus downregulating Snail1 expression, which inhibited epithelial-mesenchymal-transition (EMT) in HCC cells. Moreover, NLRX1 OE could induce cell senescence via an AKT-P21-dependent manner. CONCLUSIONS: NLRX1 acted as a tumor suppressor in HCC by inducing apoptosis, promoting senescence, and decreasing invasiveness by repressing PI3K-AKT signaling pathway. Future investigations will focus on restoring expression of NLRX1 to provide new insights into HCC treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13045-018-0573-9) contains supplementary material, which is available to authorized users. BioMed Central 2018-02-26 /pmc/articles/PMC5828065/ /pubmed/29482578 http://dx.doi.org/10.1186/s13045-018-0573-9 Text en © The Author(s). 2018 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 Hu, Bo Ding, Guang-Yu Fu, Pei-Yao Zhu, Xiao-Dong Ji, Yuan Shi, Guo-Ming Shen, Ying-Hao Cai, Jia-Bin Yang, Zhen Zhou, Jian Fan, Jia Sun, Hui-Chuan Kuang, Ming Huang, Cheng NOD-like receptor X1 functions as a tumor suppressor by inhibiting epithelial-mesenchymal transition and inducing aging in hepatocellular carcinoma cells |
title | NOD-like receptor X1 functions as a tumor suppressor by inhibiting epithelial-mesenchymal transition and inducing aging in hepatocellular carcinoma cells |
title_full | NOD-like receptor X1 functions as a tumor suppressor by inhibiting epithelial-mesenchymal transition and inducing aging in hepatocellular carcinoma cells |
title_fullStr | NOD-like receptor X1 functions as a tumor suppressor by inhibiting epithelial-mesenchymal transition and inducing aging in hepatocellular carcinoma cells |
title_full_unstemmed | NOD-like receptor X1 functions as a tumor suppressor by inhibiting epithelial-mesenchymal transition and inducing aging in hepatocellular carcinoma cells |
title_short | NOD-like receptor X1 functions as a tumor suppressor by inhibiting epithelial-mesenchymal transition and inducing aging in hepatocellular carcinoma cells |
title_sort | nod-like receptor x1 functions as a tumor suppressor by inhibiting epithelial-mesenchymal transition and inducing aging in hepatocellular carcinoma cells |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828065/ https://www.ncbi.nlm.nih.gov/pubmed/29482578 http://dx.doi.org/10.1186/s13045-018-0573-9 |
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