Upregulation of RSPO3 via targeted promoter DNA demethylation inhibits the progression of cholangiocarcinoma
Abstract Background Cholangiocarcinoma (CCA) refers to a collection of malignant tumors that develop from the biliary epithelium. Extensive clinical evidence and epidemiological observations indicate a concerning increase in both the incidence and mortality rates of CCA. Surgical resection is curren...
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| Format: | Article |
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BMC
2023-11-01
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| Series: | Clinical Epigenetics |
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| Online Access: | https://doi.org/10.1186/s13148-023-01592-9 |
| _version_ | 1797630186968055808 |
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| author | Guanhua Wu Da Wang Fei Xiong Wenzheng Liu Qi Wang Junsheng Chen Bing Wang Yongjun Chen |
| author_facet | Guanhua Wu Da Wang Fei Xiong Wenzheng Liu Qi Wang Junsheng Chen Bing Wang Yongjun Chen |
| author_sort | Guanhua Wu |
| collection | DOAJ |
| description | Abstract Background Cholangiocarcinoma (CCA) refers to a collection of malignant tumors that develop from the biliary epithelium. Extensive clinical evidence and epidemiological observations indicate a concerning increase in both the incidence and mortality rates of CCA. Surgical resection is currently the sole available cure for CCA. However, it is unfortunate that only a fraction of patients has access to surgery at the time of diagnosis. Moreover, there is a high incidence of cancer recurrence after resection, and systemic treatments have limited efficacy. Therefore, the identification of novel biomarkers for CCA-targeted molecular therapy remains a crucial task in oncology research. Results Our study demonstrated that low expression of RSPO3 was associated with poorer survival rates in patients with CCA. We found that the RSPO3 promoter DNA was hypermethylated in CCA, which was correlated with the low expression of RSPO3. The expression of RSPO3 was influenced by the balance between the DNA methyltransferase DNMT3a and the DNA demethylase TET1 in CCA. In vitro and in vivo experiments showed that targeting RSPO3 promoter DNA methylation using dCas9DNMT3a promoted tumorigenicity of CCA, while targeted RSPO3 promoter DNA demethylation using dCas9TET1CD inhibited CCA tumorigenicity. Additionally, in our primary CCA model, knockdown of Rspo3 promoted CCA progression, whereas overexpression of Rspo3 inhibited CCA progression. Conclusions Our findings suggest that increased methylation and decreased expression of RSPO3 may indicate a poor prognosis in CCA. Restoring RSPO3 expression by targeting promoter DNA demethylation could offer insights for precise treatment of CCA. |
| first_indexed | 2024-03-11T11:03:36Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1868-7083 |
| language | English |
| last_indexed | 2024-03-11T11:03:36Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj.art-b7beaa11d8de4ac19ec2f6b09e6cfb472023-11-12T12:21:13ZengBMCClinical Epigenetics1868-70832023-11-0115111410.1186/s13148-023-01592-9Upregulation of RSPO3 via targeted promoter DNA demethylation inhibits the progression of cholangiocarcinomaGuanhua Wu0Da Wang1Fei Xiong2Wenzheng Liu3Qi Wang4Junsheng Chen5Bing Wang6Yongjun Chen7Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Background Cholangiocarcinoma (CCA) refers to a collection of malignant tumors that develop from the biliary epithelium. Extensive clinical evidence and epidemiological observations indicate a concerning increase in both the incidence and mortality rates of CCA. Surgical resection is currently the sole available cure for CCA. However, it is unfortunate that only a fraction of patients has access to surgery at the time of diagnosis. Moreover, there is a high incidence of cancer recurrence after resection, and systemic treatments have limited efficacy. Therefore, the identification of novel biomarkers for CCA-targeted molecular therapy remains a crucial task in oncology research. Results Our study demonstrated that low expression of RSPO3 was associated with poorer survival rates in patients with CCA. We found that the RSPO3 promoter DNA was hypermethylated in CCA, which was correlated with the low expression of RSPO3. The expression of RSPO3 was influenced by the balance between the DNA methyltransferase DNMT3a and the DNA demethylase TET1 in CCA. In vitro and in vivo experiments showed that targeting RSPO3 promoter DNA methylation using dCas9DNMT3a promoted tumorigenicity of CCA, while targeted RSPO3 promoter DNA demethylation using dCas9TET1CD inhibited CCA tumorigenicity. Additionally, in our primary CCA model, knockdown of Rspo3 promoted CCA progression, whereas overexpression of Rspo3 inhibited CCA progression. Conclusions Our findings suggest that increased methylation and decreased expression of RSPO3 may indicate a poor prognosis in CCA. Restoring RSPO3 expression by targeting promoter DNA demethylation could offer insights for precise treatment of CCA.https://doi.org/10.1186/s13148-023-01592-9RSPO3DNA methylationTET1Targeted demethylationPrecise treatment |
| spellingShingle | Guanhua Wu Da Wang Fei Xiong Wenzheng Liu Qi Wang Junsheng Chen Bing Wang Yongjun Chen Upregulation of RSPO3 via targeted promoter DNA demethylation inhibits the progression of cholangiocarcinoma Clinical Epigenetics RSPO3 DNA methylation TET1 Targeted demethylation Precise treatment |
| title | Upregulation of RSPO3 via targeted promoter DNA demethylation inhibits the progression of cholangiocarcinoma |
| title_full | Upregulation of RSPO3 via targeted promoter DNA demethylation inhibits the progression of cholangiocarcinoma |
| title_fullStr | Upregulation of RSPO3 via targeted promoter DNA demethylation inhibits the progression of cholangiocarcinoma |
| title_full_unstemmed | Upregulation of RSPO3 via targeted promoter DNA demethylation inhibits the progression of cholangiocarcinoma |
| title_short | Upregulation of RSPO3 via targeted promoter DNA demethylation inhibits the progression of cholangiocarcinoma |
| title_sort | upregulation of rspo3 via targeted promoter dna demethylation inhibits the progression of cholangiocarcinoma |
| topic | RSPO3 DNA methylation TET1 Targeted demethylation Precise treatment |
| url | https://doi.org/10.1186/s13148-023-01592-9 |
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