FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC
Abstract Background Accumulating evidence suggests that cancer stem cells (CSCs) play a critical role in tumor initiation, progression and therapy, and recent studies have indicated that Forkhead box C1 (FOXC1) is strongly associated with CSCs. This study investigates the regulatory effects of FOXC1...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2018-09-01
|
Series: | Journal of Experimental & Clinical Cancer Research |
Subjects: | |
Online Access: | http://link.springer.com/article/10.1186/s13046-018-0894-0 |
id |
doaj-97c8dd2aa3eb4cbb986ebc1122ff038c |
---|---|
record_format |
Article |
spelling |
doaj-97c8dd2aa3eb4cbb986ebc1122ff038c2020-11-24T21:23:59ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662018-09-0137111210.1186/s13046-018-0894-0FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLCSisi Cao0Zhuo Wang1Xiujuan Gao2Wenjuan He3Yue Cai4Hui Chen5Rong Xu6Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Background Accumulating evidence suggests that cancer stem cells (CSCs) play a critical role in tumor initiation, progression and therapy, and recent studies have indicated that Forkhead box C1 (FOXC1) is strongly associated with CSCs. This study investigates the regulatory effects of FOXC1 on CSC-like properties in non-small cell lung cancer (NSCLC). Methods We analyzed FOXC1 expression in NSCLC using the Cancer Genome Atlas (TCGA) database on UALCANC and performed survival analyses of NSCLC patients on Human Protein Atlas. CSC-like properties were analyzed based on CSC marker-positive cell population, self-renewal ability, stemness-related gene expression, tumorigenicity and drug resistance. The percentage of CD133+ cells was analyzed by flow cytometric analysis. Self-renewal ability was detected by sphere-formation analysis. Real-time PCR, western blotting and immunohistochemical staining were employed to detect mRNA and protein levels. Tumorigenicity was determined based on a xenograft formation assay, and effects of FOXC1 on drug resistance were assessed by cell viability and apoptosis assays. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to investigate the binding of FOXC1 to beta-catenin promoter. Results FOXC1 expression was found to be elevated in NSCLC tissues and negatively correlated with patient survival. FOXC1 knockdown reduced CD133+ cell percentage, suppressed self-renewal ability, decreased expression of stemness-related genes (Oct4, NANOG, SOX2 and ABCG2) and inhibited NSCLC cell tumorigenicity in vivo. Moreover, FOXC1 knockdown increased cisplatin and docetaxel sensitivity and reduced gefitinib resistance, whereas FOXC1 overexpression enhanced CSC-like properties. Luciferase reporter and ChIP assays showed beta-catenin to be a direct transcriptional target of FOXC1. Furthermore, overexpression of beta-catenin reversed the CSC-like property inhibition induced by FOXC1 knockdown, and knockdown of beta-catenin attenuated the CSC-like properties induced by FOXC1 overexpression. Conclusions This study demonstrates that FOXC1 induces CSC-like properties in NSCLC by promoting beta-catenin expression. The findings indicate that FOXC1 is a potential molecular target for anti-CSC-based therapies in NSCLC.http://link.springer.com/article/10.1186/s13046-018-0894-0FOXC1Cancer stem cell-like propertiesBeta-cateninNSCLC |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sisi Cao Zhuo Wang Xiujuan Gao Wenjuan He Yue Cai Hui Chen Rong Xu |
spellingShingle |
Sisi Cao Zhuo Wang Xiujuan Gao Wenjuan He Yue Cai Hui Chen Rong Xu FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC Journal of Experimental & Clinical Cancer Research FOXC1 Cancer stem cell-like properties Beta-catenin NSCLC |
author_facet |
Sisi Cao Zhuo Wang Xiujuan Gao Wenjuan He Yue Cai Hui Chen Rong Xu |
author_sort |
Sisi Cao |
title |
FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC |
title_short |
FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC |
title_full |
FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC |
title_fullStr |
FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC |
title_full_unstemmed |
FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC |
title_sort |
foxc1 induces cancer stem cell-like properties through upregulation of beta-catenin in nsclc |
publisher |
BMC |
series |
Journal of Experimental & Clinical Cancer Research |
issn |
1756-9966 |
publishDate |
2018-09-01 |
description |
Abstract Background Accumulating evidence suggests that cancer stem cells (CSCs) play a critical role in tumor initiation, progression and therapy, and recent studies have indicated that Forkhead box C1 (FOXC1) is strongly associated with CSCs. This study investigates the regulatory effects of FOXC1 on CSC-like properties in non-small cell lung cancer (NSCLC). Methods We analyzed FOXC1 expression in NSCLC using the Cancer Genome Atlas (TCGA) database on UALCANC and performed survival analyses of NSCLC patients on Human Protein Atlas. CSC-like properties were analyzed based on CSC marker-positive cell population, self-renewal ability, stemness-related gene expression, tumorigenicity and drug resistance. The percentage of CD133+ cells was analyzed by flow cytometric analysis. Self-renewal ability was detected by sphere-formation analysis. Real-time PCR, western blotting and immunohistochemical staining were employed to detect mRNA and protein levels. Tumorigenicity was determined based on a xenograft formation assay, and effects of FOXC1 on drug resistance were assessed by cell viability and apoptosis assays. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to investigate the binding of FOXC1 to beta-catenin promoter. Results FOXC1 expression was found to be elevated in NSCLC tissues and negatively correlated with patient survival. FOXC1 knockdown reduced CD133+ cell percentage, suppressed self-renewal ability, decreased expression of stemness-related genes (Oct4, NANOG, SOX2 and ABCG2) and inhibited NSCLC cell tumorigenicity in vivo. Moreover, FOXC1 knockdown increased cisplatin and docetaxel sensitivity and reduced gefitinib resistance, whereas FOXC1 overexpression enhanced CSC-like properties. Luciferase reporter and ChIP assays showed beta-catenin to be a direct transcriptional target of FOXC1. Furthermore, overexpression of beta-catenin reversed the CSC-like property inhibition induced by FOXC1 knockdown, and knockdown of beta-catenin attenuated the CSC-like properties induced by FOXC1 overexpression. Conclusions This study demonstrates that FOXC1 induces CSC-like properties in NSCLC by promoting beta-catenin expression. The findings indicate that FOXC1 is a potential molecular target for anti-CSC-based therapies in NSCLC. |
topic |
FOXC1 Cancer stem cell-like properties Beta-catenin NSCLC |
url |
http://link.springer.com/article/10.1186/s13046-018-0894-0 |
work_keys_str_mv |
AT sisicao foxc1inducescancerstemcelllikepropertiesthroughupregulationofbetacatenininnsclc AT zhuowang foxc1inducescancerstemcelllikepropertiesthroughupregulationofbetacatenininnsclc AT xiujuangao foxc1inducescancerstemcelllikepropertiesthroughupregulationofbetacatenininnsclc AT wenjuanhe foxc1inducescancerstemcelllikepropertiesthroughupregulationofbetacatenininnsclc AT yuecai foxc1inducescancerstemcelllikepropertiesthroughupregulationofbetacatenininnsclc AT huichen foxc1inducescancerstemcelllikepropertiesthroughupregulationofbetacatenininnsclc AT rongxu foxc1inducescancerstemcelllikepropertiesthroughupregulationofbetacatenininnsclc |
_version_ |
1725990145932394496 |