MAZ promotes prostate cancer bone metastasis through transcriptionally activating the KRas-dependent RalGEFs pathway
Abstract Background Clinically, prostate cancer (PCa) exhibits a high avidity to metastasize to bone. Myc-associated zinc-finger protein (MAZ) is a well-documented oncogene involved in the progression and metastasis of multiple cancer types, even in PCa. However, the clinical significance and biolog...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-09-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-019-1374-x |
| _version_ | 1818498731944706048 |
|---|---|
| author | Qing Yang Chuandong Lang Zhengquan Wu Yuhu Dai Shaofu He Wei Guo Shuai Huang Hong Du Dong Ren Xinsheng Peng |
| author_facet | Qing Yang Chuandong Lang Zhengquan Wu Yuhu Dai Shaofu He Wei Guo Shuai Huang Hong Du Dong Ren Xinsheng Peng |
| author_sort | Qing Yang |
| collection | DOAJ |
| description | Abstract Background Clinically, prostate cancer (PCa) exhibits a high avidity to metastasize to bone. Myc-associated zinc-finger protein (MAZ) is a well-documented oncogene involved in the progression and metastasis of multiple cancer types, even in PCa. However, the clinical significance and biological roles of MAZ in bone metastasis of PCa remain unclear. Methods MAZ expression was examined in PCa tissues with bone metastasis, PCa tissues without bone metastasis and metastatic bone tissues by real-time PCR and immunohistochemistry (IHC), respectively. Statistical analysis was performed to evaluate the clinical correlation between MAZ expression and clinicopathological features and bone metastasis-free survival in PCa patients. Biological roles of MAZ in bone metastasis of PCa were investigated both in vitro by transwell assay, and in vivo by a mouse model of left cardiac ventricle inoculation. The bioinformatics analysis, western blot, pull-down assays, chromatin immunoprecipitation (ChIP) and luciferase reporter assays were applied to demonstrate and examine the relationship between MAZ and its potential downstream signalling pathway. TaqMan copy number assay was performed to identify the underlying mechanism responsible for MAZ overexpression in PCa tissues. Results MAZ expression is elevated in PCa tissues with bone metastasis compared with that in PCa tissues without bone metastasis, and is further increased in metastatic bone tissues. High expression of MAZ positively correlates with poor overall and bone metastasis-free survival in PCa patients. Upregulating MAZ elevates, while silencing MAZ represses the invasion and migration abilities of PCa cells in vitro and bone metastasis ability in vivo. Our results further reveal that MAZ promotes bone metastasis of PCa dependent on KRas signalling, although MAZ transcriptionally upregulates KRas and HRas expression, where the Ral guanine nucleotide exchange factor (RalGEF) signaling is responsible for the different roles of KRas and HRas in mediating the pro-bone metastasis of MAZ in PCa. Finally, our results indicate that recurrent gains contribute to MAZ overexpression in a small portion of PCa tissues. Conclusion These results indicate that the MAZ/Kras/ RalGEF signalling axis plays a crucial role in promoting PCa cell bone metastasis, suggesting a potential therapeutic utility of MAZ in bone metastasis of PCa. |
| first_indexed | 2024-12-10T20:19:32Z |
| format | Article |
| id | doaj.art-b23b11e28aba4765badae89366068108 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-10T20:19:32Z |
| publishDate | 2019-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-b23b11e28aba4765badae893660681082022-12-22T01:35:06ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-09-0138111710.1186/s13046-019-1374-xMAZ promotes prostate cancer bone metastasis through transcriptionally activating the KRas-dependent RalGEFs pathwayQing Yang0Chuandong Lang1Zhengquan Wu2Yuhu Dai3Shaofu He4Wei Guo5Shuai Huang6Hong Du7Dong Ren8Xinsheng Peng9Department of Orthopaedic Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopaedic Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopaedic Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopaedic Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Radiology, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopaedic Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopaedic Surgery, The Second Affiliated Hospital of Guangzhou Medical UniversityDepartment of Pathology, The First People’s Hospital of Guangzhou CityDepartment of Orthopaedic Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Orthopaedic Surgery, The First Affiliated Hospital, Sun Yat-sen UniversityAbstract Background Clinically, prostate cancer (PCa) exhibits a high avidity to metastasize to bone. Myc-associated zinc-finger protein (MAZ) is a well-documented oncogene involved in the progression and metastasis of multiple cancer types, even in PCa. However, the clinical significance and biological roles of MAZ in bone metastasis of PCa remain unclear. Methods MAZ expression was examined in PCa tissues with bone metastasis, PCa tissues without bone metastasis and metastatic bone tissues by real-time PCR and immunohistochemistry (IHC), respectively. Statistical analysis was performed to evaluate the clinical correlation between MAZ expression and clinicopathological features and bone metastasis-free survival in PCa patients. Biological roles of MAZ in bone metastasis of PCa were investigated both in vitro by transwell assay, and in vivo by a mouse model of left cardiac ventricle inoculation. The bioinformatics analysis, western blot, pull-down assays, chromatin immunoprecipitation (ChIP) and luciferase reporter assays were applied to demonstrate and examine the relationship between MAZ and its potential downstream signalling pathway. TaqMan copy number assay was performed to identify the underlying mechanism responsible for MAZ overexpression in PCa tissues. Results MAZ expression is elevated in PCa tissues with bone metastasis compared with that in PCa tissues without bone metastasis, and is further increased in metastatic bone tissues. High expression of MAZ positively correlates with poor overall and bone metastasis-free survival in PCa patients. Upregulating MAZ elevates, while silencing MAZ represses the invasion and migration abilities of PCa cells in vitro and bone metastasis ability in vivo. Our results further reveal that MAZ promotes bone metastasis of PCa dependent on KRas signalling, although MAZ transcriptionally upregulates KRas and HRas expression, where the Ral guanine nucleotide exchange factor (RalGEF) signaling is responsible for the different roles of KRas and HRas in mediating the pro-bone metastasis of MAZ in PCa. Finally, our results indicate that recurrent gains contribute to MAZ overexpression in a small portion of PCa tissues. Conclusion These results indicate that the MAZ/Kras/ RalGEF signalling axis plays a crucial role in promoting PCa cell bone metastasis, suggesting a potential therapeutic utility of MAZ in bone metastasis of PCa.http://link.springer.com/article/10.1186/s13046-019-1374-xMAZBone metastasisProstate cancerRas signallingAnd RalGEFs |
| spellingShingle | Qing Yang Chuandong Lang Zhengquan Wu Yuhu Dai Shaofu He Wei Guo Shuai Huang Hong Du Dong Ren Xinsheng Peng MAZ promotes prostate cancer bone metastasis through transcriptionally activating the KRas-dependent RalGEFs pathway Journal of Experimental & Clinical Cancer Research MAZ Bone metastasis Prostate cancer Ras signalling And RalGEFs |
| title | MAZ promotes prostate cancer bone metastasis through transcriptionally activating the KRas-dependent RalGEFs pathway |
| title_full | MAZ promotes prostate cancer bone metastasis through transcriptionally activating the KRas-dependent RalGEFs pathway |
| title_fullStr | MAZ promotes prostate cancer bone metastasis through transcriptionally activating the KRas-dependent RalGEFs pathway |
| title_full_unstemmed | MAZ promotes prostate cancer bone metastasis through transcriptionally activating the KRas-dependent RalGEFs pathway |
| title_short | MAZ promotes prostate cancer bone metastasis through transcriptionally activating the KRas-dependent RalGEFs pathway |
| title_sort | maz promotes prostate cancer bone metastasis through transcriptionally activating the kras dependent ralgefs pathway |
| topic | MAZ Bone metastasis Prostate cancer Ras signalling And RalGEFs |
| url | http://link.springer.com/article/10.1186/s13046-019-1374-x |
| work_keys_str_mv | AT qingyang mazpromotesprostatecancerbonemetastasisthroughtranscriptionallyactivatingthekrasdependentralgefspathway AT chuandonglang mazpromotesprostatecancerbonemetastasisthroughtranscriptionallyactivatingthekrasdependentralgefspathway AT zhengquanwu mazpromotesprostatecancerbonemetastasisthroughtranscriptionallyactivatingthekrasdependentralgefspathway AT yuhudai mazpromotesprostatecancerbonemetastasisthroughtranscriptionallyactivatingthekrasdependentralgefspathway AT shaofuhe mazpromotesprostatecancerbonemetastasisthroughtranscriptionallyactivatingthekrasdependentralgefspathway AT weiguo mazpromotesprostatecancerbonemetastasisthroughtranscriptionallyactivatingthekrasdependentralgefspathway AT shuaihuang mazpromotesprostatecancerbonemetastasisthroughtranscriptionallyactivatingthekrasdependentralgefspathway AT hongdu mazpromotesprostatecancerbonemetastasisthroughtranscriptionallyactivatingthekrasdependentralgefspathway AT dongren mazpromotesprostatecancerbonemetastasisthroughtranscriptionallyactivatingthekrasdependentralgefspathway AT xinshengpeng mazpromotesprostatecancerbonemetastasisthroughtranscriptionallyactivatingthekrasdependentralgefspathway |