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MST4 negatively regulates the EMT, invasion and metastasis of HCC cells by inactivating PI3K/AKT/Snail1 axis
Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a poor prognosis due to the high incidence of invasion and metastasis-related progression. However, the underlying mechanism remains elusive, and valuable biomarkers for predicting invasion, metastasis, an...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210547/ https://www.ncbi.nlm.nih.gov/pubmed/34149910 http://dx.doi.org/10.7150/jca.60008 |
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author | Dian, Mei-Juan Li, Jing Zhang, Xiao-Ling Li, Zi-Jian Zhou, Ying Zhou, Wei Zhong, Qiu-Ling Pang, Wen-Qian Lin, Xiao-Lin Liu, Tao Liu, Yi-An Li, Yong-Long Han, Liu-Xin Zhao, Wen-Tao Jia, Jun-Shuang Xiao, Sheng-Jun Xiao, Dong Xia, Jia-Wei Hao, Wei-Chao |
author_facet | Dian, Mei-Juan Li, Jing Zhang, Xiao-Ling Li, Zi-Jian Zhou, Ying Zhou, Wei Zhong, Qiu-Ling Pang, Wen-Qian Lin, Xiao-Lin Liu, Tao Liu, Yi-An Li, Yong-Long Han, Liu-Xin Zhao, Wen-Tao Jia, Jun-Shuang Xiao, Sheng-Jun Xiao, Dong Xia, Jia-Wei Hao, Wei-Chao |
author_sort | Dian, Mei-Juan |
collection | PubMed |
description | Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a poor prognosis due to the high incidence of invasion and metastasis-related progression. However, the underlying mechanism remains elusive, and valuable biomarkers for predicting invasion, metastasis, and poor prognosis of HCC patients are still lacking. Methods: Immunohistochemistry (IHC) was performed on HCC tissues (n = 325), and the correlations between MST4 expression of the clinical HCC tissues, the clinicopathologic features, and survival were further evaluated. The effects of MST4 on HCC cell migratory and invasive properties in vitro were evaluated by Transwell and Boyden assays. The intrahepatic metastasis mouse model was established to evaluate the HCC metastasis in vivo. The PI3K inhibitor, LY294002, and a specific siRNA against Snail1 were used to investigate the roles of PI3K/AKT pathway and Snail1 in MST4-regulated EMT, migration, and invasion of HCC cells, respectively. Results: In this study, by comprehensively analyzing our clinical data, we discovered that low MST4 expression is highly associated with the advanced progression of HCC and serves as a prognostic biomarker for HCC patients of clinical-stage III-IV. Functional studies indicate that MST4 inactivation induces epithelial-to-mesenchymal transition (EMT) of HCC cells, promotes their migratory and invasive potential in vitro, and facilitates their intrahepatic metastasis in vivo, whereas MST4 overexpression exhibits the opposite phenotypes. Mechanistically, MST4 inactivation elevates the expression and nuclear translocation of Snail1, a key EMT transcription factor (EMT-TF), through the PI3K/AKT signaling pathway, thus inducing the EMT phenotype of HCC cells, and enhancing their invasive and metastatic potential. Moreover, a negative correlation between MST4 and p-AKT, Snail1, and Ki67 and a positive correlation between MST4 and E-cadherin were determined in clinical HCC samples. Conclusions: Our findings indicate that MST4 suppresses EMT, invasion, and metastasis of HCC cells by modulating the PI3K/AKT/Snail1 axis, suggesting that MST4 may be a potential prognostic biomarker for aggressive and metastatic HCC. |
format | Online Article Text |
id | pubmed-8210547 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-82105472021-06-17 MST4 negatively regulates the EMT, invasion and metastasis of HCC cells by inactivating PI3K/AKT/Snail1 axis Dian, Mei-Juan Li, Jing Zhang, Xiao-Ling Li, Zi-Jian Zhou, Ying Zhou, Wei Zhong, Qiu-Ling Pang, Wen-Qian Lin, Xiao-Lin Liu, Tao Liu, Yi-An Li, Yong-Long Han, Liu-Xin Zhao, Wen-Tao Jia, Jun-Shuang Xiao, Sheng-Jun Xiao, Dong Xia, Jia-Wei Hao, Wei-Chao J Cancer Research Paper Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a poor prognosis due to the high incidence of invasion and metastasis-related progression. However, the underlying mechanism remains elusive, and valuable biomarkers for predicting invasion, metastasis, and poor prognosis of HCC patients are still lacking. Methods: Immunohistochemistry (IHC) was performed on HCC tissues (n = 325), and the correlations between MST4 expression of the clinical HCC tissues, the clinicopathologic features, and survival were further evaluated. The effects of MST4 on HCC cell migratory and invasive properties in vitro were evaluated by Transwell and Boyden assays. The intrahepatic metastasis mouse model was established to evaluate the HCC metastasis in vivo. The PI3K inhibitor, LY294002, and a specific siRNA against Snail1 were used to investigate the roles of PI3K/AKT pathway and Snail1 in MST4-regulated EMT, migration, and invasion of HCC cells, respectively. Results: In this study, by comprehensively analyzing our clinical data, we discovered that low MST4 expression is highly associated with the advanced progression of HCC and serves as a prognostic biomarker for HCC patients of clinical-stage III-IV. Functional studies indicate that MST4 inactivation induces epithelial-to-mesenchymal transition (EMT) of HCC cells, promotes their migratory and invasive potential in vitro, and facilitates their intrahepatic metastasis in vivo, whereas MST4 overexpression exhibits the opposite phenotypes. Mechanistically, MST4 inactivation elevates the expression and nuclear translocation of Snail1, a key EMT transcription factor (EMT-TF), through the PI3K/AKT signaling pathway, thus inducing the EMT phenotype of HCC cells, and enhancing their invasive and metastatic potential. Moreover, a negative correlation between MST4 and p-AKT, Snail1, and Ki67 and a positive correlation between MST4 and E-cadherin were determined in clinical HCC samples. Conclusions: Our findings indicate that MST4 suppresses EMT, invasion, and metastasis of HCC cells by modulating the PI3K/AKT/Snail1 axis, suggesting that MST4 may be a potential prognostic biomarker for aggressive and metastatic HCC. Ivyspring International Publisher 2021-05-27 /pmc/articles/PMC8210547/ /pubmed/34149910 http://dx.doi.org/10.7150/jca.60008 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Dian, Mei-Juan Li, Jing Zhang, Xiao-Ling Li, Zi-Jian Zhou, Ying Zhou, Wei Zhong, Qiu-Ling Pang, Wen-Qian Lin, Xiao-Lin Liu, Tao Liu, Yi-An Li, Yong-Long Han, Liu-Xin Zhao, Wen-Tao Jia, Jun-Shuang Xiao, Sheng-Jun Xiao, Dong Xia, Jia-Wei Hao, Wei-Chao MST4 negatively regulates the EMT, invasion and metastasis of HCC cells by inactivating PI3K/AKT/Snail1 axis |
title | MST4 negatively regulates the EMT, invasion and metastasis of HCC cells by inactivating PI3K/AKT/Snail1 axis |
title_full | MST4 negatively regulates the EMT, invasion and metastasis of HCC cells by inactivating PI3K/AKT/Snail1 axis |
title_fullStr | MST4 negatively regulates the EMT, invasion and metastasis of HCC cells by inactivating PI3K/AKT/Snail1 axis |
title_full_unstemmed | MST4 negatively regulates the EMT, invasion and metastasis of HCC cells by inactivating PI3K/AKT/Snail1 axis |
title_short | MST4 negatively regulates the EMT, invasion and metastasis of HCC cells by inactivating PI3K/AKT/Snail1 axis |
title_sort | mst4 negatively regulates the emt, invasion and metastasis of hcc cells by inactivating pi3k/akt/snail1 axis |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210547/ https://www.ncbi.nlm.nih.gov/pubmed/34149910 http://dx.doi.org/10.7150/jca.60008 |
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