NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner
Abstract Background Hepatocellular carcinoma is the third top cause of cancer-related mortalities worldwide. The prognosis of HCC patients remains poor due to rapid progression and high incidence of tumor recurrence. Nicastrin (NCSTN), a core subunit of γ-Secretase, has been reported to play a vital...
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BMC
2020-07-01
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Series: | Journal of Experimental & Clinical Cancer Research |
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Online Access: | http://link.springer.com/article/10.1186/s13046-020-01638-3 |
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doaj-cb87b84aa0d2492787903e4ffd02f7e2 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hui Li Tian Lan Lin Xu Hailing Liu Jinju Wang Jiaxin Li Xiangzheng Chen Jiwei Huang Xuefeng Li Kefei Yuan Yong Zeng Hong Wu |
spellingShingle |
Hui Li Tian Lan Lin Xu Hailing Liu Jinju Wang Jiaxin Li Xiangzheng Chen Jiwei Huang Xuefeng Li Kefei Yuan Yong Zeng Hong Wu NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner Journal of Experimental & Clinical Cancer Research Hepatocellular carcinoma γ-Secretase Nicastrin Epithelial–mesenchymal transition β-Catenin |
author_facet |
Hui Li Tian Lan Lin Xu Hailing Liu Jinju Wang Jiaxin Li Xiangzheng Chen Jiwei Huang Xuefeng Li Kefei Yuan Yong Zeng Hong Wu |
author_sort |
Hui Li |
title |
NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner |
title_short |
NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner |
title_full |
NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner |
title_fullStr |
NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner |
title_full_unstemmed |
NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner |
title_sort |
ncstn promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a notch1/akt dependent manner |
publisher |
BMC |
series |
Journal of Experimental & Clinical Cancer Research |
issn |
1756-9966 |
publishDate |
2020-07-01 |
description |
Abstract Background Hepatocellular carcinoma is the third top cause of cancer-related mortalities worldwide. The prognosis of HCC patients remains poor due to rapid progression and high incidence of tumor recurrence. Nicastrin (NCSTN), a core subunit of γ-Secretase, has been reported to play a vital role in tumor progression. However, no study till now has revealed its role in HCC. Methods The expression of NCSTN was evaluated by immunohistochemical staining, Western blot, and quantitative real-time PCR. Cell counting kit-8, colony formation and cell cycle assays were used for evaluating cell growth in vitro. Transwell and wound-healing assays were used for evaluating cell migration and invasion capacity. Immunofluorescence, subcellular protein fractionation and co-immunoprecipitation were used for location analysis of β-catenin. The in vivo functions of NCSTN were illustrated by xenograft tumor models. Results NCSTN was dramatically overexpressed in HCC compared to normal liver tissues. Elevated NCSTN expression level was significantly correlated to worse overall and recurrence-free survival of HCC patients. Enhanced NCSTN expression promoted HCC cell growth, migration and invasion in vitro and in vivo. Mechanistic investigations showed that NCSTN induced epithelial-mesenchymal transition (EMT) process via upregulation of Zeb1. Subsequently, we revealed that NCSTN facilitated nuclear translocation of β-catenin, a positive transcriptional regulator of Zeb1. Using Notch and AKT inhibitors, we revealed that NCSTN promoted β-catenin activation through Notch1 and AKT signaling pathway. NCSTN increased AKT and GSK-3β phosphorylation by cleavage of Notch1, which decreased GSK-3β/β-catenin complex. The inactivation of GSK-3β inhibited the β-catenin degradation and promoted nuclear translocation of β-catenin to initiate transcription of Zeb1, resulting in malignant phenotype. Conclusions Our results demonstrated that NCSTN promoted HCC cell growth and metastasis via β-catenin-mediated upregulation of Zeb1 in a Notch1/AKT dependent manner, suggesting that NCSTN might serve as a potential prognostic marker and therapeutic target for HCC. |
topic |
Hepatocellular carcinoma γ-Secretase Nicastrin Epithelial–mesenchymal transition β-Catenin |
url |
http://link.springer.com/article/10.1186/s13046-020-01638-3 |
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doaj-cb87b84aa0d2492787903e4ffd02f7e22020-11-25T03:32:34ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662020-07-0139111810.1186/s13046-020-01638-3NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent mannerHui Li0Tian Lan1Lin Xu2Hailing Liu3Jinju Wang4Jiaxin Li5Xiangzheng Chen6Jiwei Huang7Xuefeng Li8Kefei Yuan9Yong Zeng10Hong Wu11Department of Liver Surgery, Liver Transplantation Division, Laboratory of Liver Surgery, West China Hospital, Sichuan UniversityDepartment of Liver Surgery, Liver Transplantation Division, Laboratory of Liver Surgery, West China Hospital, Sichuan UniversityLaboratory of Liver Surgery, West China Hospital, Sichuan UniversityDepartment of Liver Surgery, Liver Transplantation Division, Laboratory of Liver Surgery, West China Hospital, Sichuan UniversityDepartment of Liver Surgery, Liver Transplantation Division, Laboratory of Liver Surgery, West China Hospital, Sichuan UniversityDepartment of Liver Surgery, Liver Transplantation Division, Laboratory of Liver Surgery, West China Hospital, Sichuan UniversityDepartment of Liver Surgery, Liver Transplantation Division, Laboratory of Liver Surgery, West China Hospital, Sichuan UniversityDepartment of Liver Surgery, Liver Transplantation Division, Laboratory of Liver Surgery, West China Hospital, Sichuan UniversitySchool of Basic Medical Sciences, Guangzhou Medical UniversityDepartment of Liver Surgery, Liver Transplantation Division, Laboratory of Liver Surgery, West China Hospital, Sichuan UniversityDepartment of Liver Surgery, Liver Transplantation Division, Laboratory of Liver Surgery, West China Hospital, Sichuan UniversityDepartment of Liver Surgery, Liver Transplantation Division, Laboratory of Liver Surgery, West China Hospital, Sichuan UniversityAbstract Background Hepatocellular carcinoma is the third top cause of cancer-related mortalities worldwide. The prognosis of HCC patients remains poor due to rapid progression and high incidence of tumor recurrence. Nicastrin (NCSTN), a core subunit of γ-Secretase, has been reported to play a vital role in tumor progression. However, no study till now has revealed its role in HCC. Methods The expression of NCSTN was evaluated by immunohistochemical staining, Western blot, and quantitative real-time PCR. Cell counting kit-8, colony formation and cell cycle assays were used for evaluating cell growth in vitro. Transwell and wound-healing assays were used for evaluating cell migration and invasion capacity. Immunofluorescence, subcellular protein fractionation and co-immunoprecipitation were used for location analysis of β-catenin. The in vivo functions of NCSTN were illustrated by xenograft tumor models. Results NCSTN was dramatically overexpressed in HCC compared to normal liver tissues. Elevated NCSTN expression level was significantly correlated to worse overall and recurrence-free survival of HCC patients. Enhanced NCSTN expression promoted HCC cell growth, migration and invasion in vitro and in vivo. Mechanistic investigations showed that NCSTN induced epithelial-mesenchymal transition (EMT) process via upregulation of Zeb1. Subsequently, we revealed that NCSTN facilitated nuclear translocation of β-catenin, a positive transcriptional regulator of Zeb1. Using Notch and AKT inhibitors, we revealed that NCSTN promoted β-catenin activation through Notch1 and AKT signaling pathway. NCSTN increased AKT and GSK-3β phosphorylation by cleavage of Notch1, which decreased GSK-3β/β-catenin complex. The inactivation of GSK-3β inhibited the β-catenin degradation and promoted nuclear translocation of β-catenin to initiate transcription of Zeb1, resulting in malignant phenotype. Conclusions Our results demonstrated that NCSTN promoted HCC cell growth and metastasis via β-catenin-mediated upregulation of Zeb1 in a Notch1/AKT dependent manner, suggesting that NCSTN might serve as a potential prognostic marker and therapeutic target for HCC.http://link.springer.com/article/10.1186/s13046-020-01638-3Hepatocellular carcinomaγ-SecretaseNicastrinEpithelial–mesenchymal transitionβ-Catenin |