Inhibition of CCCTC Binding Factor-Programmed Cell Death Ligand 1 Axis Suppresses Emergence of Chemoresistance Induced by Gastric Cancer-Derived Mesenchymal Stem Cells
BackgroundGastric cancer (GC) is the third leading cause of cancer-associated deaths worldwide. Stromal cells, especially mesenchymal stem cells (MSCs), play significant roles in the development of therapy resistance depending on their paracrine function. The PD-1/PD-L1 crosstalk between cancer and...
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| Format: | Article |
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.884373/full |
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| author | Qianqian Wang Chao Huang Ying Ding Shaodi Wen Xin Wang Shuwei Guo Qiuzhi Gao Zhihong Chen Yuanyuan Zhao Mei Wang Bo Shen Wei Zhu |
| author_facet | Qianqian Wang Chao Huang Ying Ding Shaodi Wen Xin Wang Shuwei Guo Qiuzhi Gao Zhihong Chen Yuanyuan Zhao Mei Wang Bo Shen Wei Zhu |
| author_sort | Qianqian Wang |
| collection | DOAJ |
| description | BackgroundGastric cancer (GC) is the third leading cause of cancer-associated deaths worldwide. Stromal cells, especially mesenchymal stem cells (MSCs), play significant roles in the development of therapy resistance depending on their paracrine function. The PD-1/PD-L1 crosstalk between cancer and immune cells has been well studied. Emerging evidence suggests that PD-L1 also contributes to tumor resistance to therapy.MethodsCell survival and apoptosis were assessed using CCK-8, colony formation, and flow cytometry assays. Protein alterations were analyzed via Western blot. Gene knockdown and overexpression were achieved with siRNA/shRNA and lentiviral infection, respectively. Drug effects on tumors in vivo were assessed with xenografts in nude mice. In addition, GC patient samples after chemotherapy treatment were collected to observe the relationship between chemotherapy effect and CTCF or PD-L1.ResultsIn response to 5-fluorouracil or paclitaxel treatment, GCMSC-CM enhanced the cell viability and decreased the apoptosis rate. Furthermore, blocking PD-L1 or CTCF in GC cells prevented GCMSC-induced drug resistance accompanied by a decline in cell stemness. Consistent with these in vitro observations, mice treated with GCMSC-CM showed a lower sensitivity to 5-fluorouracil. In addition, high expression of CTCF and PD-L1 was associated with poor chemotherapy progression in the clinic.ConclusionStudy results demonstrate a mechanism where GCMSC-CM promotes GC chemoresistance by upregulating CTCF-PD-L1 and provide strong evidence in support of targeting CTCF-PD-L1 signaling as a strategy to prevent resistance in the clinic. |
| first_indexed | 2024-12-10T10:07:27Z |
| format | Article |
| id | doaj.art-cc2be6689ec54f59bbcd8b27aa67dcdd |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-10T10:07:27Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-cc2be6689ec54f59bbcd8b27aa67dcdd2022-12-22T01:53:13ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-04-011310.3389/fimmu.2022.884373884373Inhibition of CCCTC Binding Factor-Programmed Cell Death Ligand 1 Axis Suppresses Emergence of Chemoresistance Induced by Gastric Cancer-Derived Mesenchymal Stem CellsQianqian Wang0Chao Huang1Ying Ding2Shaodi Wen3Xin Wang4Shuwei Guo5Qiuzhi Gao6Zhihong Chen7Yuanyuan Zhao8Mei Wang9Bo Shen10Wei Zhu11School of Medicine, Jiangsu University, Zhenjiang, ChinaSchool of Medicine, Jiangsu University, Zhenjiang, ChinaSchool of Medicine, Jiangsu University, Zhenjiang, ChinaDepartment of Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, ChinaDepartment of Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, ChinaSchool of Medicine, Jiangsu University, Zhenjiang, ChinaSchool of Medicine, Jiangsu University, Zhenjiang, ChinaDepartment of Gastrointestinal Surgery, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, ChinaSchool of Medicine, Jiangsu University, Zhenjiang, ChinaSchool of Medicine, Jiangsu University, Zhenjiang, ChinaDepartment of Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, ChinaSchool of Medicine, Jiangsu University, Zhenjiang, ChinaBackgroundGastric cancer (GC) is the third leading cause of cancer-associated deaths worldwide. Stromal cells, especially mesenchymal stem cells (MSCs), play significant roles in the development of therapy resistance depending on their paracrine function. The PD-1/PD-L1 crosstalk between cancer and immune cells has been well studied. Emerging evidence suggests that PD-L1 also contributes to tumor resistance to therapy.MethodsCell survival and apoptosis were assessed using CCK-8, colony formation, and flow cytometry assays. Protein alterations were analyzed via Western blot. Gene knockdown and overexpression were achieved with siRNA/shRNA and lentiviral infection, respectively. Drug effects on tumors in vivo were assessed with xenografts in nude mice. In addition, GC patient samples after chemotherapy treatment were collected to observe the relationship between chemotherapy effect and CTCF or PD-L1.ResultsIn response to 5-fluorouracil or paclitaxel treatment, GCMSC-CM enhanced the cell viability and decreased the apoptosis rate. Furthermore, blocking PD-L1 or CTCF in GC cells prevented GCMSC-induced drug resistance accompanied by a decline in cell stemness. Consistent with these in vitro observations, mice treated with GCMSC-CM showed a lower sensitivity to 5-fluorouracil. In addition, high expression of CTCF and PD-L1 was associated with poor chemotherapy progression in the clinic.ConclusionStudy results demonstrate a mechanism where GCMSC-CM promotes GC chemoresistance by upregulating CTCF-PD-L1 and provide strong evidence in support of targeting CTCF-PD-L1 signaling as a strategy to prevent resistance in the clinic.https://www.frontiersin.org/articles/10.3389/fimmu.2022.884373/fullmesenchymal stem cellsgastric cancer5-FUpaclitaxelPD-L1CTCF |
| spellingShingle | Qianqian Wang Chao Huang Ying Ding Shaodi Wen Xin Wang Shuwei Guo Qiuzhi Gao Zhihong Chen Yuanyuan Zhao Mei Wang Bo Shen Wei Zhu Inhibition of CCCTC Binding Factor-Programmed Cell Death Ligand 1 Axis Suppresses Emergence of Chemoresistance Induced by Gastric Cancer-Derived Mesenchymal Stem Cells Frontiers in Immunology mesenchymal stem cells gastric cancer 5-FU paclitaxel PD-L1 CTCF |
| title | Inhibition of CCCTC Binding Factor-Programmed Cell Death Ligand 1 Axis Suppresses Emergence of Chemoresistance Induced by Gastric Cancer-Derived Mesenchymal Stem Cells |
| title_full | Inhibition of CCCTC Binding Factor-Programmed Cell Death Ligand 1 Axis Suppresses Emergence of Chemoresistance Induced by Gastric Cancer-Derived Mesenchymal Stem Cells |
| title_fullStr | Inhibition of CCCTC Binding Factor-Programmed Cell Death Ligand 1 Axis Suppresses Emergence of Chemoresistance Induced by Gastric Cancer-Derived Mesenchymal Stem Cells |
| title_full_unstemmed | Inhibition of CCCTC Binding Factor-Programmed Cell Death Ligand 1 Axis Suppresses Emergence of Chemoresistance Induced by Gastric Cancer-Derived Mesenchymal Stem Cells |
| title_short | Inhibition of CCCTC Binding Factor-Programmed Cell Death Ligand 1 Axis Suppresses Emergence of Chemoresistance Induced by Gastric Cancer-Derived Mesenchymal Stem Cells |
| title_sort | inhibition of ccctc binding factor programmed cell death ligand 1 axis suppresses emergence of chemoresistance induced by gastric cancer derived mesenchymal stem cells |
| topic | mesenchymal stem cells gastric cancer 5-FU paclitaxel PD-L1 CTCF |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.884373/full |
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