CHIP functions as an oncogene by promoting colorectal cancer metastasis via activation of MAPK and AKT signaling and suppression of E-cadherin
Abstract Background The carboxyl terminus of Hsc70-interacting protein (CHIP) is an E3 ubiquitin ligase that plays a controversial role in different cancers, either as a tumor suppressor or a tumor promoter. To date, the exact function and underlying mechanism of CHIP in colorectal cancer (CRC) is n...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-06-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12967-018-1540-5 |
| _version_ | 1818172361891905536 |
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| author | Jingjing Xu Jun Zhou Hanjue Dai Fei Liu Wenjing Li Wenjuan Wang Feng Guo |
| author_facet | Jingjing Xu Jun Zhou Hanjue Dai Fei Liu Wenjing Li Wenjuan Wang Feng Guo |
| author_sort | Jingjing Xu |
| collection | DOAJ |
| description | Abstract Background The carboxyl terminus of Hsc70-interacting protein (CHIP) is an E3 ubiquitin ligase that plays a controversial role in different cancers, either as a tumor suppressor or a tumor promoter. To date, the exact function and underlying mechanism of CHIP in colorectal cancer (CRC) is not yet clear. Here we aimed to determine whether CHIP could affect the biological behaviors of CRC cells and its underlying mechanisms. Methods Stably transfected CHIP overexpression and depletion DLD-1 and HT-29 cells were established using Lipofectamine 2000. Cell growth was monitored by x-Celligence system. Cell proliferation was detected using CCK-8 and Brdu proliferation assay. Cell apoptosis and cell cycle were detected by flow cytometry analysis. Cell migration and invasion abilities were monitored by x-Celligence system, wound healing assay and transwell assay. In vivo intraperitoneal metastasis assay was performed to investigate the influence of CHIP on the tumor metastasis of CRC cells in nude mice. The expression of ERK, AKT, NF-кB signaling subunits and EMT related proteins were detected by Western blotting. The influence and function of CHIP on the protein expression of CRC cells were also elucidated by liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis. CRC microarray tissue was analyzed to investigate the CHIP expression and its clinical significance. Results CHIP depletion inhibited cell growth, migration and invasion potential of CRC cells, accompanied by downregulation of MAPK and AKT signaling activities and upregulation of E-cadherin. CHIP overexpression dramatically enhanced the migration and invasion abilities, due to the upregulation of MAPK and AKT signaling and downregulation of E-cadherin. The proteomic analysis confirmed that E-cadherin was decreased in CHIP-overexpressing CRC cells. Furthermore, clinical tissue data revealed that CHIP expression was upregulated in CRC samples and was significantly correlated with poor survival of CRC patients. Mechanically, CHIP probably activated the MAPK and AKT signaling, which inactivated GSK-3β. The GSK-3β inactivation, in turn, upregulated Slug and led to E-cadherin downregulation and EMT initiation. Conclusions Our finding suggested that CHIP functions as an oncogene in the migration and metastasis of CRC, and is a potential unfavorable independent predictive biomarker for CRC. CHIP activates the AKT pathway to promote EMT and metastasis in CRC through the CHIP-MAPK/AKT-GSK-3β-Slug-E-cadherin pathways. |
| first_indexed | 2024-12-11T19:11:24Z |
| format | Article |
| id | doaj.art-7a6803de62b64752a14410e0bd015ac1 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-12-11T19:11:24Z |
| publishDate | 2018-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-7a6803de62b64752a14410e0bd015ac12022-12-22T00:53:46ZengBMCJournal of Translational Medicine1479-58762018-06-0116111910.1186/s12967-018-1540-5CHIP functions as an oncogene by promoting colorectal cancer metastasis via activation of MAPK and AKT signaling and suppression of E-cadherinJingjing Xu0Jun Zhou1Hanjue Dai2Fei Liu3Wenjing Li4Wenjuan Wang5Feng Guo6Center for Clinical Laboratory, The First Affiliated Hospital of Soochow UniversityCenter for Clinical Laboratory, The First Affiliated Hospital of Soochow UniversityDepartment of Oncology, The First Affiliated Hospital of Soochow UniversityDepartment of Gastroenterology, The First Affiliated Hospital of Soochow UniversityDepartment of Oncology, The First Affiliated Hospital of Soochow UniversityState Key Laboratory of Microbial Technology, School of Life Sciences, Shandong UniversityDepartment of Oncology, Nanjing Medical University Affiliated Suzhou HospitalAbstract Background The carboxyl terminus of Hsc70-interacting protein (CHIP) is an E3 ubiquitin ligase that plays a controversial role in different cancers, either as a tumor suppressor or a tumor promoter. To date, the exact function and underlying mechanism of CHIP in colorectal cancer (CRC) is not yet clear. Here we aimed to determine whether CHIP could affect the biological behaviors of CRC cells and its underlying mechanisms. Methods Stably transfected CHIP overexpression and depletion DLD-1 and HT-29 cells were established using Lipofectamine 2000. Cell growth was monitored by x-Celligence system. Cell proliferation was detected using CCK-8 and Brdu proliferation assay. Cell apoptosis and cell cycle were detected by flow cytometry analysis. Cell migration and invasion abilities were monitored by x-Celligence system, wound healing assay and transwell assay. In vivo intraperitoneal metastasis assay was performed to investigate the influence of CHIP on the tumor metastasis of CRC cells in nude mice. The expression of ERK, AKT, NF-кB signaling subunits and EMT related proteins were detected by Western blotting. The influence and function of CHIP on the protein expression of CRC cells were also elucidated by liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis. CRC microarray tissue was analyzed to investigate the CHIP expression and its clinical significance. Results CHIP depletion inhibited cell growth, migration and invasion potential of CRC cells, accompanied by downregulation of MAPK and AKT signaling activities and upregulation of E-cadherin. CHIP overexpression dramatically enhanced the migration and invasion abilities, due to the upregulation of MAPK and AKT signaling and downregulation of E-cadherin. The proteomic analysis confirmed that E-cadherin was decreased in CHIP-overexpressing CRC cells. Furthermore, clinical tissue data revealed that CHIP expression was upregulated in CRC samples and was significantly correlated with poor survival of CRC patients. Mechanically, CHIP probably activated the MAPK and AKT signaling, which inactivated GSK-3β. The GSK-3β inactivation, in turn, upregulated Slug and led to E-cadherin downregulation and EMT initiation. Conclusions Our finding suggested that CHIP functions as an oncogene in the migration and metastasis of CRC, and is a potential unfavorable independent predictive biomarker for CRC. CHIP activates the AKT pathway to promote EMT and metastasis in CRC through the CHIP-MAPK/AKT-GSK-3β-Slug-E-cadherin pathways.http://link.springer.com/article/10.1186/s12967-018-1540-5CHIPColorectal cancerOncogeneMetastasisEpithelial–mesenchymal transition |
| spellingShingle | Jingjing Xu Jun Zhou Hanjue Dai Fei Liu Wenjing Li Wenjuan Wang Feng Guo CHIP functions as an oncogene by promoting colorectal cancer metastasis via activation of MAPK and AKT signaling and suppression of E-cadherin Journal of Translational Medicine CHIP Colorectal cancer Oncogene Metastasis Epithelial–mesenchymal transition |
| title | CHIP functions as an oncogene by promoting colorectal cancer metastasis via activation of MAPK and AKT signaling and suppression of E-cadherin |
| title_full | CHIP functions as an oncogene by promoting colorectal cancer metastasis via activation of MAPK and AKT signaling and suppression of E-cadherin |
| title_fullStr | CHIP functions as an oncogene by promoting colorectal cancer metastasis via activation of MAPK and AKT signaling and suppression of E-cadherin |
| title_full_unstemmed | CHIP functions as an oncogene by promoting colorectal cancer metastasis via activation of MAPK and AKT signaling and suppression of E-cadherin |
| title_short | CHIP functions as an oncogene by promoting colorectal cancer metastasis via activation of MAPK and AKT signaling and suppression of E-cadherin |
| title_sort | chip functions as an oncogene by promoting colorectal cancer metastasis via activation of mapk and akt signaling and suppression of e cadherin |
| topic | CHIP Colorectal cancer Oncogene Metastasis Epithelial–mesenchymal transition |
| url | http://link.springer.com/article/10.1186/s12967-018-1540-5 |
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