AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination
Abstract Background Cancer stem cells (CSCs) are regarded as the "seed cells" for tumorigenesis, metastasis, recurrence and drug resistance. However, specific surface markers of CSCs of different origins have not been documented. Methods Single-cell sequencing was used to analyze the highl...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-11-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-022-02532-w |
| _version_ | 1798016725415886848 |
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| author | Rou Zhao Baoyu He Qingli Bie Jinghe Cao Haoran Lu Zhixin Zhang Jing Liang Li Wei Huabao Xiong Bin Zhang |
| author_facet | Rou Zhao Baoyu He Qingli Bie Jinghe Cao Haoran Lu Zhixin Zhang Jing Liang Li Wei Huabao Xiong Bin Zhang |
| author_sort | Rou Zhao |
| collection | DOAJ |
| description | Abstract Background Cancer stem cells (CSCs) are regarded as the "seed cells" for tumorigenesis, metastasis, recurrence and drug resistance. However, specific surface markers of CSCs of different origins have not been documented. Methods Single-cell sequencing was used to analyze the highly expressed genes in cancer stem cells of gastric cancer patients, and it was verified that AQP5 was specifically highly expressed in gastric cancer stem cells (GC-CSCs) in vivo and in vitro. The effect of AQP5-promoting LGR5 on the malignant biological function of GC-CSCs was investigated. The mechanism by which AQP5 affects GC-CSCs was explored through transcriptome sequencing, proteomic detection, mass spectrometry, etc. Results We report the identification and validation of AQP5 as a potentially specific surface marker of GC-CSCs. AQP5 was significantly upregulated in CSCs isolated from gastric cancer patients and in spheroid cells, and AQP5 was coexpressed with the canonical stem marker LGR5. Biologically, AQP5 promoted the sphere formation, proliferation, migration and invasion of GC cells in vitro and enhanced tumorigenesis in vivo. Furthermore, AQP5 coordinated with LGR5 and synergistically promoted the tumorigenesis of GC-CSCs. At the mechanistic level, AQP5 activated autophagy by inducing the LC3I/LC3II transformation in GC-CSCs, which was crucial for the biological functions of AQP5. Finally, we demonstrated that AQP5 recruited the E3 ligase TRIM21 to the key autophagy protein ULK1 and induced the K63-mediated ubiquitination of ULK1. Conclusions We elucidate a novel surface marker, AQP5, which is specifically expressed by GC-CSCs. Furthermore, our study creates a link between AQP5 and LGR5 and highlights the necessity of targeting both surface markers simultaneously as a promising approach for the treatment of gastric cancer patients. |
| first_indexed | 2024-04-11T15:55:17Z |
| format | Article |
| id | doaj.art-06d233450a3d4706b9e87c289fb0891c |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-11T15:55:17Z |
| publishDate | 2022-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-06d233450a3d4706b9e87c289fb0891c2022-12-22T04:15:11ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662022-11-0141111510.1186/s13046-022-02532-wAQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitinationRou Zhao0Baoyu He1Qingli Bie2Jinghe Cao3Haoran Lu4Zhixin Zhang5Jing Liang6Li Wei7Huabao Xiong8Bin Zhang9Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical UniversityDepartment of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical UniversityDepartment of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical UniversityDepartment of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical UniversityDepartment of Hepatobiliary Surgery, Affiliated Hospital of Jining Medical University, Jining Medical UniversityDepartment of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining Medical UniversityDepartment of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical UniversityDepartment of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical UniversityInstitute of Immunology and Molecular Medicine, Jining Medical UniversityDepartment of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical UniversityAbstract Background Cancer stem cells (CSCs) are regarded as the "seed cells" for tumorigenesis, metastasis, recurrence and drug resistance. However, specific surface markers of CSCs of different origins have not been documented. Methods Single-cell sequencing was used to analyze the highly expressed genes in cancer stem cells of gastric cancer patients, and it was verified that AQP5 was specifically highly expressed in gastric cancer stem cells (GC-CSCs) in vivo and in vitro. The effect of AQP5-promoting LGR5 on the malignant biological function of GC-CSCs was investigated. The mechanism by which AQP5 affects GC-CSCs was explored through transcriptome sequencing, proteomic detection, mass spectrometry, etc. Results We report the identification and validation of AQP5 as a potentially specific surface marker of GC-CSCs. AQP5 was significantly upregulated in CSCs isolated from gastric cancer patients and in spheroid cells, and AQP5 was coexpressed with the canonical stem marker LGR5. Biologically, AQP5 promoted the sphere formation, proliferation, migration and invasion of GC cells in vitro and enhanced tumorigenesis in vivo. Furthermore, AQP5 coordinated with LGR5 and synergistically promoted the tumorigenesis of GC-CSCs. At the mechanistic level, AQP5 activated autophagy by inducing the LC3I/LC3II transformation in GC-CSCs, which was crucial for the biological functions of AQP5. Finally, we demonstrated that AQP5 recruited the E3 ligase TRIM21 to the key autophagy protein ULK1 and induced the K63-mediated ubiquitination of ULK1. Conclusions We elucidate a novel surface marker, AQP5, which is specifically expressed by GC-CSCs. Furthermore, our study creates a link between AQP5 and LGR5 and highlights the necessity of targeting both surface markers simultaneously as a promising approach for the treatment of gastric cancer patients.https://doi.org/10.1186/s13046-022-02532-wCancer stem cellsAQP5LGR5AutophagyULK1Gastric cancer |
| spellingShingle | Rou Zhao Baoyu He Qingli Bie Jinghe Cao Haoran Lu Zhixin Zhang Jing Liang Li Wei Huabao Xiong Bin Zhang AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination Journal of Experimental & Clinical Cancer Research Cancer stem cells AQP5 LGR5 Autophagy ULK1 Gastric cancer |
| title | AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination |
| title_full | AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination |
| title_fullStr | AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination |
| title_full_unstemmed | AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination |
| title_short | AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination |
| title_sort | aqp5 complements lgr5 to determine the fates of gastric cancer stem cells through regulating ulk1 ubiquitination |
| topic | Cancer stem cells AQP5 LGR5 Autophagy ULK1 Gastric cancer |
| url | https://doi.org/10.1186/s13046-022-02532-w |
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