Genome-Wide Screening Identifies Gene AKR1C1 Critical for Resistance to Pirarubicin in Bladder Cancer
Non-muscle-invasive bladder cancer (NMIBC) is a common tumor of the urinary system. Given its high rates of recurrence, progression, and drug resistance, NMIBC seriously affects the quality of life and limits the survival time of patients. Pirarubicin (THP) is a bladder infusion chemotherapy drug re...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/9/2487 |
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| author | Zhenyu Nie Yuanhui Gao Mei Chen Yanling Peng Na Guo Hui Cao Denggao Huang Xin Gao Shufang Zhang |
| author_facet | Zhenyu Nie Yuanhui Gao Mei Chen Yanling Peng Na Guo Hui Cao Denggao Huang Xin Gao Shufang Zhang |
| author_sort | Zhenyu Nie |
| collection | DOAJ |
| description | Non-muscle-invasive bladder cancer (NMIBC) is a common tumor of the urinary system. Given its high rates of recurrence, progression, and drug resistance, NMIBC seriously affects the quality of life and limits the survival time of patients. Pirarubicin (THP) is a bladder infusion chemotherapy drug recommended by the guidelines for NMIBC. Although the widespread use of THP reduces the recurrence rate of NMIBC, 10–50% of patients still suffer from tumor recurrence, which is closely related to tumor resistance to chemotherapy drugs. This study was performed to screen the critical genes causing THP resistance in bladder cancer cell lines by using the CRISPR/dCas9-SAM system. Thus, AKR1C1 was screened. Results showed that the high expression of AKR1C1 could enhance the drug resistance of bladder cancer to THP both in vivo and in vitro. This gene could reduce the levels of 4-hydroxynonenal and reactive oxygen species (ROS) and resist THP-induced apoptosis. However, AKR1C1 did not affect the proliferation, invasion, or migration of the bladder cancer cells. Aspirin, which is an AKR1C1 inhibitor, could help reduce the drug resistance caused by AKR1C1. After receiving THP treatment, the bladder cancer cell lines could upregulate the expression of the AKR1C1 gene through the ROS/KEAP1/NRF2 pathway, leading to resistance to THP treatment. Using tempol, which is an inhibitor of ROS, could prevent the upregulation of AKR1C1 expression. |
| first_indexed | 2024-03-11T04:22:36Z |
| format | Article |
| id | doaj.art-cca3f21f47544a1789967163fe643fc3 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T04:22:36Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-cca3f21f47544a1789967163fe643fc32023-11-17T22:40:25ZengMDPI AGCancers2072-66942023-04-01159248710.3390/cancers15092487Genome-Wide Screening Identifies Gene AKR1C1 Critical for Resistance to Pirarubicin in Bladder CancerZhenyu Nie0Yuanhui Gao1Mei Chen2Yanling Peng3Na Guo4Hui Cao5Denggao Huang6Xin Gao7Shufang Zhang8Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou 570208, ChinaCentral Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou 570208, ChinaCentral Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou 570208, ChinaCentral Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou 570208, ChinaCentral Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou 570208, ChinaCentral Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou 570208, ChinaCentral Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou 570208, ChinaGraduate School of Chinese Academy of Medical Sciences & Peking Union Medical College, Tsinghua University, Beijing 100190, ChinaCentral Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou 570208, ChinaNon-muscle-invasive bladder cancer (NMIBC) is a common tumor of the urinary system. Given its high rates of recurrence, progression, and drug resistance, NMIBC seriously affects the quality of life and limits the survival time of patients. Pirarubicin (THP) is a bladder infusion chemotherapy drug recommended by the guidelines for NMIBC. Although the widespread use of THP reduces the recurrence rate of NMIBC, 10–50% of patients still suffer from tumor recurrence, which is closely related to tumor resistance to chemotherapy drugs. This study was performed to screen the critical genes causing THP resistance in bladder cancer cell lines by using the CRISPR/dCas9-SAM system. Thus, AKR1C1 was screened. Results showed that the high expression of AKR1C1 could enhance the drug resistance of bladder cancer to THP both in vivo and in vitro. This gene could reduce the levels of 4-hydroxynonenal and reactive oxygen species (ROS) and resist THP-induced apoptosis. However, AKR1C1 did not affect the proliferation, invasion, or migration of the bladder cancer cells. Aspirin, which is an AKR1C1 inhibitor, could help reduce the drug resistance caused by AKR1C1. After receiving THP treatment, the bladder cancer cell lines could upregulate the expression of the AKR1C1 gene through the ROS/KEAP1/NRF2 pathway, leading to resistance to THP treatment. Using tempol, which is an inhibitor of ROS, could prevent the upregulation of AKR1C1 expression.https://www.mdpi.com/2072-6694/15/9/2487CRISPR/dCas9-SAMbladder cancerpirarubicindrug resistanceAKR1C1 |
| spellingShingle | Zhenyu Nie Yuanhui Gao Mei Chen Yanling Peng Na Guo Hui Cao Denggao Huang Xin Gao Shufang Zhang Genome-Wide Screening Identifies Gene AKR1C1 Critical for Resistance to Pirarubicin in Bladder Cancer Cancers CRISPR/dCas9-SAM bladder cancer pirarubicin drug resistance AKR1C1 |
| title | Genome-Wide Screening Identifies Gene AKR1C1 Critical for Resistance to Pirarubicin in Bladder Cancer |
| title_full | Genome-Wide Screening Identifies Gene AKR1C1 Critical for Resistance to Pirarubicin in Bladder Cancer |
| title_fullStr | Genome-Wide Screening Identifies Gene AKR1C1 Critical for Resistance to Pirarubicin in Bladder Cancer |
| title_full_unstemmed | Genome-Wide Screening Identifies Gene AKR1C1 Critical for Resistance to Pirarubicin in Bladder Cancer |
| title_short | Genome-Wide Screening Identifies Gene AKR1C1 Critical for Resistance to Pirarubicin in Bladder Cancer |
| title_sort | genome wide screening identifies gene akr1c1 critical for resistance to pirarubicin in bladder cancer |
| topic | CRISPR/dCas9-SAM bladder cancer pirarubicin drug resistance AKR1C1 |
| url | https://www.mdpi.com/2072-6694/15/9/2487 |
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