Targeting circDGKD Intercepts TKI’s Effects on Up-Regulation of Estrogen Receptor β and Vasculogenic Mimicry in Renal Cell Carcinoma
Vasculogenic mimicry (VM) has been reported as an alternative channel to increase tumor nutrient supplies and accelerate tumor progression, and is associated with poor survival prognosis in multiple cancers, including renal cell carcinoma (RCC). The currently used anti-angiogenic treatment for metas...
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MDPI AG
2022-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/7/1639 |
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| author | Jie Ding Xin-Gang Cui Hao-Jie Chen Yin Sun Wei-Wei Yu Jie Luo Guang-Qian Xiao Chawnshang Chang Jun Qi Shuyuan Yeh |
| author_facet | Jie Ding Xin-Gang Cui Hao-Jie Chen Yin Sun Wei-Wei Yu Jie Luo Guang-Qian Xiao Chawnshang Chang Jun Qi Shuyuan Yeh |
| author_sort | Jie Ding |
| collection | DOAJ |
| description | Vasculogenic mimicry (VM) has been reported as an alternative channel to increase tumor nutrient supplies and accelerate tumor progression, and is associated with poor survival prognosis in multiple cancers, including renal cell carcinoma (RCC). The currently used anti-angiogenic treatment for metastatic RCC, sunitinib, a tyrosine kinase inhibitor (TKI), has been reported to induce VM formation. Previously we identified that the estrogen receptor β (ERβ) functions as an oncogenic factor to promote RCC progression, supported by the analytic results from The Cancer Genome Atlas (TCGA) database. We have also found evidence that sunitinib induces RCC VM formation by up-regulating ERβ expression. In this study, we further demonstrated that treatment with sunitinib, as well as axitinib, another TKI, could induce ERβ expression in RCC cell lines. Clinical clear cell RCC (ccRCC) patients with higher ERβ expression are more likely to be found VE-cadherin positive and VM positive. Mechanism dissection showed that TKI- induced ERβ transcriptionally up-regulates the circular RNA of DGKD (circDGKD, hsa_circ_0058763), which enhances VE-cadherin expression by sponging the microRNA miR-125-5p family. Targeting circDGKD intercepts sunitinib-pretreatment-induced RCC VM formation, reduces metastases and improves survival in an experimental orthotopic animal model. Targeting ERβ/circDGKD signals may improve the TKI efficacy and provide novel combination therapies for metastatic RCC. |
| first_indexed | 2024-03-09T12:05:03Z |
| format | Article |
| id | doaj.art-c0134a94c4b04f3eaeeb15f220dcc6d0 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T12:05:03Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-c0134a94c4b04f3eaeeb15f220dcc6d02023-11-30T22:59:56ZengMDPI AGCancers2072-66942022-03-01147163910.3390/cancers14071639Targeting circDGKD Intercepts TKI’s Effects on Up-Regulation of Estrogen Receptor β and Vasculogenic Mimicry in Renal Cell CarcinomaJie Ding0Xin-Gang Cui1Hao-Jie Chen2Yin Sun3Wei-Wei Yu4Jie Luo5Guang-Qian Xiao6Chawnshang Chang7Jun Qi8Shuyuan Yeh9Urology Department, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, ChinaUrology Department, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, ChinaUrology Department, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, ChinaGeorge H. Whipple Lab for Cancer Research, Departments of Urology, Pathology and the Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USAGeorge H. Whipple Lab for Cancer Research, Departments of Urology, Pathology and the Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USAGeorge H. Whipple Lab for Cancer Research, Departments of Urology, Pathology and the Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USADepartment of Pathology and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USAGeorge H. Whipple Lab for Cancer Research, Departments of Urology, Pathology and the Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USAUrology Department, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, ChinaGeorge H. Whipple Lab for Cancer Research, Departments of Urology, Pathology and the Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USAVasculogenic mimicry (VM) has been reported as an alternative channel to increase tumor nutrient supplies and accelerate tumor progression, and is associated with poor survival prognosis in multiple cancers, including renal cell carcinoma (RCC). The currently used anti-angiogenic treatment for metastatic RCC, sunitinib, a tyrosine kinase inhibitor (TKI), has been reported to induce VM formation. Previously we identified that the estrogen receptor β (ERβ) functions as an oncogenic factor to promote RCC progression, supported by the analytic results from The Cancer Genome Atlas (TCGA) database. We have also found evidence that sunitinib induces RCC VM formation by up-regulating ERβ expression. In this study, we further demonstrated that treatment with sunitinib, as well as axitinib, another TKI, could induce ERβ expression in RCC cell lines. Clinical clear cell RCC (ccRCC) patients with higher ERβ expression are more likely to be found VE-cadherin positive and VM positive. Mechanism dissection showed that TKI- induced ERβ transcriptionally up-regulates the circular RNA of DGKD (circDGKD, hsa_circ_0058763), which enhances VE-cadherin expression by sponging the microRNA miR-125-5p family. Targeting circDGKD intercepts sunitinib-pretreatment-induced RCC VM formation, reduces metastases and improves survival in an experimental orthotopic animal model. Targeting ERβ/circDGKD signals may improve the TKI efficacy and provide novel combination therapies for metastatic RCC.https://www.mdpi.com/2072-6694/14/7/1639estrogen receptor βvasculogenic mimicryrenal cell carcinomacircular RNAVE-cadherin |
| spellingShingle | Jie Ding Xin-Gang Cui Hao-Jie Chen Yin Sun Wei-Wei Yu Jie Luo Guang-Qian Xiao Chawnshang Chang Jun Qi Shuyuan Yeh Targeting circDGKD Intercepts TKI’s Effects on Up-Regulation of Estrogen Receptor β and Vasculogenic Mimicry in Renal Cell Carcinoma Cancers estrogen receptor β vasculogenic mimicry renal cell carcinoma circular RNA VE-cadherin |
| title | Targeting circDGKD Intercepts TKI’s Effects on Up-Regulation of Estrogen Receptor β and Vasculogenic Mimicry in Renal Cell Carcinoma |
| title_full | Targeting circDGKD Intercepts TKI’s Effects on Up-Regulation of Estrogen Receptor β and Vasculogenic Mimicry in Renal Cell Carcinoma |
| title_fullStr | Targeting circDGKD Intercepts TKI’s Effects on Up-Regulation of Estrogen Receptor β and Vasculogenic Mimicry in Renal Cell Carcinoma |
| title_full_unstemmed | Targeting circDGKD Intercepts TKI’s Effects on Up-Regulation of Estrogen Receptor β and Vasculogenic Mimicry in Renal Cell Carcinoma |
| title_short | Targeting circDGKD Intercepts TKI’s Effects on Up-Regulation of Estrogen Receptor β and Vasculogenic Mimicry in Renal Cell Carcinoma |
| title_sort | targeting circdgkd intercepts tki s effects on up regulation of estrogen receptor β and vasculogenic mimicry in renal cell carcinoma |
| topic | estrogen receptor β vasculogenic mimicry renal cell carcinoma circular RNA VE-cadherin |
| url | https://www.mdpi.com/2072-6694/14/7/1639 |
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