BMX-ARHGAP fusion protein maintains the tumorigenicity of gastric cancer stem cells by activating the JAK/STAT3 signaling pathway
Abstract Background Cancer stem cells (CSCs), drug-resistant cancer cell subsets, are known to be responsible for tumor metastasis and relapse. The JAK/STAT pathway, activated by SH2 domain, is known to regulate the tumor growth in gastric cancer (GC). Now, this study was designed to examine whether...
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doaj-6f9d12490eaa4766ad935c9bc52d45252020-11-25T02:36:34ZengBMCCancer Cell International1475-28672019-05-0119111510.1186/s12935-019-0847-5BMX-ARHGAP fusion protein maintains the tumorigenicity of gastric cancer stem cells by activating the JAK/STAT3 signaling pathwayXiao-Feng Xu0Feng Gao1Jian-Jiang Wang2Cong Long3Xing Chen4Lan Tao5Liu Yang6Li Ding7Yong Ji8Clinical Laboratory, Jingjiang People’s HospitalDepartment of Surgery, Jingjiang People’s HospitalDepartment of Surgery, Jingjiang People’s HospitalClinical Laboratory, Jingjiang People’s HospitalDepartment of Surgery, Jingjiang People’s HospitalCentral Laboratory, Jingjiang People’s HospitalClinical Laboratory, Jingjiang People’s HospitalClinical Laboratory, Jingjiang People’s HospitalDepartment of Surgery, Jingjiang People’s HospitalAbstract Background Cancer stem cells (CSCs), drug-resistant cancer cell subsets, are known to be responsible for tumor metastasis and relapse. The JAK/STAT pathway, activated by SH2 domain, is known to regulate the tumor growth in gastric cancer (GC). Now, this study was designed to examine whether BMX-ARHGAP affects the GC stem cell properties and the underlying regulatory network via JAK/STAT axis. Methods BMX-ARHGAP expression was characterized in GC tissues and cells by RT-qPCR and western blot assay. When BMX-ARHGAP was overexpressed or silenced via plasmids or siRNA transfection, the stem cell properties were assessed by determining stem cell markers CD133, CD44, SOX2 and Nanog, followed by cell sphere and colony formation assays. Subsequently, cell proliferation and invasion were examined by conducting EdU and Transwell assays. The JAK/STAT3 signaling pathway activation was inhibited using AG490. ARHGAP12, BMX exon 10–11, BXM-SH2, JAK2 and STAT3 expression patterns were all determined to examine the regulatory network. The stem cell property in nude mice was also tested. Results BMX-ARHGAP was determined to be enriched in the GC. Overexpression of BMX-ARHGAP resulted in increased expression of CD133, CD44, SOX2 and Nanog protein, and accelerated proliferation and invasion of CD133+CD44+ cells as well as facilitated self-renewal potential of GC cells. However, the inhibition of the JAK/STAT3 signaling pathway reversed the stimulating effect of BMX-ARHGAP on proliferative and invasion abilities of CD133+CD44+ cells. The overexpression of BMX-ARHGAP was suggested to increase the BMX-SH2 protein expression via ARHGAP 5′UTR, and activate the JAK/STAT3 signaling pathway. Also, BMX-ARHGAP promoted tumor growth in nude mice. Conclusions The aforementioned results demonstrated that the BMX-ARHGAP-dependent SH2 domain-JAK/STAT3 axis mediates the maintenance of GC stem cells, benefiting the development of new potential therapeutic targets for GC.http://link.springer.com/article/10.1186/s12935-019-0847-5BMX-ARHGAPSrc homology region 2Gastric cancerJAK/STAT3 signaling pathwayCancer stem cells |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xiao-Feng Xu Feng Gao Jian-Jiang Wang Cong Long Xing Chen Lan Tao Liu Yang Li Ding Yong Ji |
spellingShingle |
Xiao-Feng Xu Feng Gao Jian-Jiang Wang Cong Long Xing Chen Lan Tao Liu Yang Li Ding Yong Ji BMX-ARHGAP fusion protein maintains the tumorigenicity of gastric cancer stem cells by activating the JAK/STAT3 signaling pathway Cancer Cell International BMX-ARHGAP Src homology region 2 Gastric cancer JAK/STAT3 signaling pathway Cancer stem cells |
author_facet |
Xiao-Feng Xu Feng Gao Jian-Jiang Wang Cong Long Xing Chen Lan Tao Liu Yang Li Ding Yong Ji |
author_sort |
Xiao-Feng Xu |
title |
BMX-ARHGAP fusion protein maintains the tumorigenicity of gastric cancer stem cells by activating the JAK/STAT3 signaling pathway |
title_short |
BMX-ARHGAP fusion protein maintains the tumorigenicity of gastric cancer stem cells by activating the JAK/STAT3 signaling pathway |
title_full |
BMX-ARHGAP fusion protein maintains the tumorigenicity of gastric cancer stem cells by activating the JAK/STAT3 signaling pathway |
title_fullStr |
BMX-ARHGAP fusion protein maintains the tumorigenicity of gastric cancer stem cells by activating the JAK/STAT3 signaling pathway |
title_full_unstemmed |
BMX-ARHGAP fusion protein maintains the tumorigenicity of gastric cancer stem cells by activating the JAK/STAT3 signaling pathway |
title_sort |
bmx-arhgap fusion protein maintains the tumorigenicity of gastric cancer stem cells by activating the jak/stat3 signaling pathway |
publisher |
BMC |
series |
Cancer Cell International |
issn |
1475-2867 |
publishDate |
2019-05-01 |
description |
Abstract Background Cancer stem cells (CSCs), drug-resistant cancer cell subsets, are known to be responsible for tumor metastasis and relapse. The JAK/STAT pathway, activated by SH2 domain, is known to regulate the tumor growth in gastric cancer (GC). Now, this study was designed to examine whether BMX-ARHGAP affects the GC stem cell properties and the underlying regulatory network via JAK/STAT axis. Methods BMX-ARHGAP expression was characterized in GC tissues and cells by RT-qPCR and western blot assay. When BMX-ARHGAP was overexpressed or silenced via plasmids or siRNA transfection, the stem cell properties were assessed by determining stem cell markers CD133, CD44, SOX2 and Nanog, followed by cell sphere and colony formation assays. Subsequently, cell proliferation and invasion were examined by conducting EdU and Transwell assays. The JAK/STAT3 signaling pathway activation was inhibited using AG490. ARHGAP12, BMX exon 10–11, BXM-SH2, JAK2 and STAT3 expression patterns were all determined to examine the regulatory network. The stem cell property in nude mice was also tested. Results BMX-ARHGAP was determined to be enriched in the GC. Overexpression of BMX-ARHGAP resulted in increased expression of CD133, CD44, SOX2 and Nanog protein, and accelerated proliferation and invasion of CD133+CD44+ cells as well as facilitated self-renewal potential of GC cells. However, the inhibition of the JAK/STAT3 signaling pathway reversed the stimulating effect of BMX-ARHGAP on proliferative and invasion abilities of CD133+CD44+ cells. The overexpression of BMX-ARHGAP was suggested to increase the BMX-SH2 protein expression via ARHGAP 5′UTR, and activate the JAK/STAT3 signaling pathway. Also, BMX-ARHGAP promoted tumor growth in nude mice. Conclusions The aforementioned results demonstrated that the BMX-ARHGAP-dependent SH2 domain-JAK/STAT3 axis mediates the maintenance of GC stem cells, benefiting the development of new potential therapeutic targets for GC. |
topic |
BMX-ARHGAP Src homology region 2 Gastric cancer JAK/STAT3 signaling pathway Cancer stem cells |
url |
http://link.springer.com/article/10.1186/s12935-019-0847-5 |
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