Tumorigenesis of basal muscle invasive bladder cancer was mediated by PTEN protein degradation resulting from SNHG1 upregulation
Abstract Background Phosphatase and tensin homolog deleted on chromosome ten (PTEN) serves as a powerful tumor suppressor, and has been found to be downregulated in human bladder cancer (BC) tissues. Despite this observation, the mechanisms contributing to PTEN’s downregulation have remained elusive...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-024-02966-4 |
| _version_ | 1797272749575503872 |
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| author | Tengda Li Maowen Huang Ning Sun Xiaohui Hua Ruifan Chen Qipeng Xie Shirui Huang Mengxiang Du Yazhen Zhao Qianqian Lin Jiheng Xu Xiaoyun Han Yunping Zhao Zhongxian Tian Yu Zhang Wei Chen Xian Shen Chuanshu Huang |
| author_facet | Tengda Li Maowen Huang Ning Sun Xiaohui Hua Ruifan Chen Qipeng Xie Shirui Huang Mengxiang Du Yazhen Zhao Qianqian Lin Jiheng Xu Xiaoyun Han Yunping Zhao Zhongxian Tian Yu Zhang Wei Chen Xian Shen Chuanshu Huang |
| author_sort | Tengda Li |
| collection | DOAJ |
| description | Abstract Background Phosphatase and tensin homolog deleted on chromosome ten (PTEN) serves as a powerful tumor suppressor, and has been found to be downregulated in human bladder cancer (BC) tissues. Despite this observation, the mechanisms contributing to PTEN’s downregulation have remained elusive. Methods We established targeted genes’ knockdown or overexpressed cell lines to explore the mechanism how it drove the malignant transformation of urothelial cells or promoted anchorageindependent growth of human basal muscle invasive BC (BMIBC) cells. The mice model was used to validate the conclusion in vivo. The important findings were also extended to human studies. Results In this study, we discovered that mice exposed to N-butyl-N-(4-hydroxybu-tyl)nitrosamine (BBN), a specific bladder chemical carcinogen, exhibited primary BMIBC accompanied by a pronounced reduction in PTEN protein expression in vivo. Utilizing a lncRNA deep sequencing high-throughput platform, along with gain- and loss-of-function analyses, we identified small nucleolar RNA host gene 1 (SNHG1) as a critical lncRNA that might drive the formation of primary BMIBCs in BBN-treated mice. Cell culture results further demonstrated that BBN exposure significantly induced SNHG1 in normal human bladder urothelial cell UROtsa. Notably, the ectopic expression of SNHG1 alone was sufficient to induce malignant transformation in human urothelial cells, while SNHG1 knockdown effectively inhibited anchorage-independent growth of human BMIBCs. Our detailed investigation revealed that SNHG1 overexpression led to PTEN protein degradation through its direct interaction with HUR. This interaction reduced HUR binding to ubiquitin-specific peptidase 8 (USP8) mRNA, causing degradation of USP8 mRNA and a subsequent decrease in USP8 protein expression. The downregulation of USP8, in turn, increased PTEN polyubiquitination and degradation, culminating in cell malignant transformation and BMIBC anchorageindependent growth. In vivo studies confirmed the downregulation of PTEN and USP8, as well as their positive correlations in both BBN-treated mouse bladder urothelium and tumor tissues of bladder cancer in nude mice. Conclusions Our findings, for the first time, demonstrate that overexpressed SNHG1 competes with USP8 for binding to HUR. This competition attenuates USP8 mRNA stability and protein expression, leading to PTEN protein degradation, consequently, this process drives urothelial cell malignant transformation and fosters BMIBC growth and primary BMIBC formation. |
| first_indexed | 2024-03-07T14:34:36Z |
| format | Article |
| id | doaj.art-421aba319a3b4ff184b485eef418a03a |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-03-07T14:34:36Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-421aba319a3b4ff184b485eef418a03a2024-03-05T20:43:34ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662024-02-0143111810.1186/s13046-024-02966-4Tumorigenesis of basal muscle invasive bladder cancer was mediated by PTEN protein degradation resulting from SNHG1 upregulationTengda Li0Maowen Huang1Ning Sun2Xiaohui Hua3Ruifan Chen4Qipeng Xie5Shirui Huang6Mengxiang Du7Yazhen Zhao8Qianqian Lin9Jiheng Xu10Xiaoyun Han11Yunping Zhao12Zhongxian Tian13Yu Zhang14Wei Chen15Xian Shen16Chuanshu Huang17Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityThe First Affiliated Hospital of Wenzhou Medical UniversityThe First Affiliated Hospital of Wenzhou Medical UniversityOujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityAbstract Background Phosphatase and tensin homolog deleted on chromosome ten (PTEN) serves as a powerful tumor suppressor, and has been found to be downregulated in human bladder cancer (BC) tissues. Despite this observation, the mechanisms contributing to PTEN’s downregulation have remained elusive. Methods We established targeted genes’ knockdown or overexpressed cell lines to explore the mechanism how it drove the malignant transformation of urothelial cells or promoted anchorageindependent growth of human basal muscle invasive BC (BMIBC) cells. The mice model was used to validate the conclusion in vivo. The important findings were also extended to human studies. Results In this study, we discovered that mice exposed to N-butyl-N-(4-hydroxybu-tyl)nitrosamine (BBN), a specific bladder chemical carcinogen, exhibited primary BMIBC accompanied by a pronounced reduction in PTEN protein expression in vivo. Utilizing a lncRNA deep sequencing high-throughput platform, along with gain- and loss-of-function analyses, we identified small nucleolar RNA host gene 1 (SNHG1) as a critical lncRNA that might drive the formation of primary BMIBCs in BBN-treated mice. Cell culture results further demonstrated that BBN exposure significantly induced SNHG1 in normal human bladder urothelial cell UROtsa. Notably, the ectopic expression of SNHG1 alone was sufficient to induce malignant transformation in human urothelial cells, while SNHG1 knockdown effectively inhibited anchorage-independent growth of human BMIBCs. Our detailed investigation revealed that SNHG1 overexpression led to PTEN protein degradation through its direct interaction with HUR. This interaction reduced HUR binding to ubiquitin-specific peptidase 8 (USP8) mRNA, causing degradation of USP8 mRNA and a subsequent decrease in USP8 protein expression. The downregulation of USP8, in turn, increased PTEN polyubiquitination and degradation, culminating in cell malignant transformation and BMIBC anchorageindependent growth. In vivo studies confirmed the downregulation of PTEN and USP8, as well as their positive correlations in both BBN-treated mouse bladder urothelium and tumor tissues of bladder cancer in nude mice. Conclusions Our findings, for the first time, demonstrate that overexpressed SNHG1 competes with USP8 for binding to HUR. This competition attenuates USP8 mRNA stability and protein expression, leading to PTEN protein degradation, consequently, this process drives urothelial cell malignant transformation and fosters BMIBC growth and primary BMIBC formation.https://doi.org/10.1186/s13046-024-02966-4lncRNA SNHG1PTENUSP8Bladder cancer |
| spellingShingle | Tengda Li Maowen Huang Ning Sun Xiaohui Hua Ruifan Chen Qipeng Xie Shirui Huang Mengxiang Du Yazhen Zhao Qianqian Lin Jiheng Xu Xiaoyun Han Yunping Zhao Zhongxian Tian Yu Zhang Wei Chen Xian Shen Chuanshu Huang Tumorigenesis of basal muscle invasive bladder cancer was mediated by PTEN protein degradation resulting from SNHG1 upregulation Journal of Experimental & Clinical Cancer Research lncRNA SNHG1 PTEN USP8 Bladder cancer |
| title | Tumorigenesis of basal muscle invasive bladder cancer was mediated by PTEN protein degradation resulting from SNHG1 upregulation |
| title_full | Tumorigenesis of basal muscle invasive bladder cancer was mediated by PTEN protein degradation resulting from SNHG1 upregulation |
| title_fullStr | Tumorigenesis of basal muscle invasive bladder cancer was mediated by PTEN protein degradation resulting from SNHG1 upregulation |
| title_full_unstemmed | Tumorigenesis of basal muscle invasive bladder cancer was mediated by PTEN protein degradation resulting from SNHG1 upregulation |
| title_short | Tumorigenesis of basal muscle invasive bladder cancer was mediated by PTEN protein degradation resulting from SNHG1 upregulation |
| title_sort | tumorigenesis of basal muscle invasive bladder cancer was mediated by pten protein degradation resulting from snhg1 upregulation |
| topic | lncRNA SNHG1 PTEN USP8 Bladder cancer |
| url | https://doi.org/10.1186/s13046-024-02966-4 |
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