Platinum drugs upregulate CXCR4 and PD‐L1 expression via ROS‐dependent pathways, with implications for novel combined treatment in gastric cancer
Abstract CXC chemokine receptor 4 (CXCR4) and programmed cell death‐ligand 1 (PD‐L1) are two critical molecules involved in the tumor immune microenvironment. However, the impact of platinum drugs, such as cisplatin, on CXCR4 or PD‐L1 expression and the underlying mechanisms in gastric cancer (GC) r...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-01-01
|
| Series: | The Journal of Pathology: Clinical Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/2056-4538.70015 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832583865096470528 |
|---|---|
| author | Xiaoyu Kang Lin Zhang Shushang Liu Fei Wang Haiming Liu Fenli Zhou Fei Wu Haohao Zhang Daiming Fan Yongzhan Nie Zhangqian Chen |
| author_facet | Xiaoyu Kang Lin Zhang Shushang Liu Fei Wang Haiming Liu Fenli Zhou Fei Wu Haohao Zhang Daiming Fan Yongzhan Nie Zhangqian Chen |
| author_sort | Xiaoyu Kang |
| collection | DOAJ |
| description | Abstract CXC chemokine receptor 4 (CXCR4) and programmed cell death‐ligand 1 (PD‐L1) are two critical molecules involved in the tumor immune microenvironment. However, the impact of platinum drugs, such as cisplatin, on CXCR4 or PD‐L1 expression and the underlying mechanisms in gastric cancer (GC) remain unknown. Moreover, the correlation between their expression levels in GC remains elusive. Immunohistochemistry, western blot, and RT‐qPCR were performed to determine the expression pattern of CXCR4 and PD‐L1 in GC. Clinical samples, patient‐derived xenografts, and cell‐derived xenografts were utilized to investigate the effects of platinum drugs on the expression levels of CXCR4 and PD‐L1. Postchemotherapy resected GC tumor tissues showed higher CXCR4 and PD‐L1 expression levels than pretreatment biopsies (p < 0.05). Similarly, GC xenografts treated with platinum‐based chemotherapy exhibited increased CXCR4 and PD‐L1 expression levels compared to saline‐treated controls (p < 0.05). A positive correlation was detected between the expression levels of CXCR4 and PD‐L1 in GC tumor tissues. Increased levels of CXCR4 and PD‐L1 expression, in a dose‐ and time‐dependent manner upon cisplatin treatment, were observed in GC cells (p < 0.05). Cisplatin‐induced CXCR4 upregulation relies on ROS/HIF‐1α and ROS/NF‐κB pathways, while cisplatin‐induced PD‐L1 upregulation is cyclic GMP‐AMP synthase/stimulator of IFN genes‐dependent and associated with elevated ROS levels in GC cells. CXCR4 expression was found to be positively correlated with PD‐L1 expression in GC. Platinum drugs upregulated the levels of CXCR4 and PD‐L1 expression in GC. A combined strategy targeting CXCR‐4 and PD‐L1 might have clinical prospects for GC patients. |
| format | Article |
| id | doaj-art-c07f52c79fff4eca98fde4200a1f9493 |
| institution | Kabale University |
| issn | 2056-4538 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | The Journal of Pathology: Clinical Research |
| spelling | doaj-art-c07f52c79fff4eca98fde4200a1f94932025-01-28T03:40:31ZengWileyThe Journal of Pathology: Clinical Research2056-45382025-01-01111n/an/a10.1002/2056-4538.70015Platinum drugs upregulate CXCR4 and PD‐L1 expression via ROS‐dependent pathways, with implications for novel combined treatment in gastric cancerXiaoyu Kang0Lin Zhang1Shushang Liu2Fei Wang3Haiming Liu4Fenli Zhou5Fei Wu6Haohao Zhang7Daiming Fan8Yongzhan Nie9Zhangqian Chen10State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases Fourth Military Medical University Xi'an PR ChinaDepartment of Internal Medicine Central Medical Branch of Chinese PLA General Hospital Beijing PR ChinaDepartment of Digestive Surgery, Xijing Hospital of Digestive Diseases Fourth Military Medical University Xi'an PR ChinaDepartment of Digestive Surgery, Honghui Hospital Xi'an Jiaotong University Xi'an PR ChinaSchool of Software Engineering Beijing Jiaotong University Beijing PR ChinaState Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases Fourth Military Medical University Xi'an PR ChinaDepartment of Urology, Shandong Provincial Hospital Shandong First Medical University Jinan PR ChinaDepartment of Digestive Surgery, Honghui Hospital Xi'an Jiaotong University Xi'an PR ChinaState Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases Fourth Military Medical University Xi'an PR ChinaState Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases Fourth Military Medical University Xi'an PR ChinaState Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases Fourth Military Medical University Xi'an PR ChinaAbstract CXC chemokine receptor 4 (CXCR4) and programmed cell death‐ligand 1 (PD‐L1) are two critical molecules involved in the tumor immune microenvironment. However, the impact of platinum drugs, such as cisplatin, on CXCR4 or PD‐L1 expression and the underlying mechanisms in gastric cancer (GC) remain unknown. Moreover, the correlation between their expression levels in GC remains elusive. Immunohistochemistry, western blot, and RT‐qPCR were performed to determine the expression pattern of CXCR4 and PD‐L1 in GC. Clinical samples, patient‐derived xenografts, and cell‐derived xenografts were utilized to investigate the effects of platinum drugs on the expression levels of CXCR4 and PD‐L1. Postchemotherapy resected GC tumor tissues showed higher CXCR4 and PD‐L1 expression levels than pretreatment biopsies (p < 0.05). Similarly, GC xenografts treated with platinum‐based chemotherapy exhibited increased CXCR4 and PD‐L1 expression levels compared to saline‐treated controls (p < 0.05). A positive correlation was detected between the expression levels of CXCR4 and PD‐L1 in GC tumor tissues. Increased levels of CXCR4 and PD‐L1 expression, in a dose‐ and time‐dependent manner upon cisplatin treatment, were observed in GC cells (p < 0.05). Cisplatin‐induced CXCR4 upregulation relies on ROS/HIF‐1α and ROS/NF‐κB pathways, while cisplatin‐induced PD‐L1 upregulation is cyclic GMP‐AMP synthase/stimulator of IFN genes‐dependent and associated with elevated ROS levels in GC cells. CXCR4 expression was found to be positively correlated with PD‐L1 expression in GC. Platinum drugs upregulated the levels of CXCR4 and PD‐L1 expression in GC. A combined strategy targeting CXCR‐4 and PD‐L1 might have clinical prospects for GC patients.https://doi.org/10.1002/2056-4538.70015CXCR4PD‐L1gastric cancercisplatintreatment strategy |
| spellingShingle | Xiaoyu Kang Lin Zhang Shushang Liu Fei Wang Haiming Liu Fenli Zhou Fei Wu Haohao Zhang Daiming Fan Yongzhan Nie Zhangqian Chen Platinum drugs upregulate CXCR4 and PD‐L1 expression via ROS‐dependent pathways, with implications for novel combined treatment in gastric cancer The Journal of Pathology: Clinical Research CXCR4 PD‐L1 gastric cancer cisplatin treatment strategy |
| title | Platinum drugs upregulate CXCR4 and PD‐L1 expression via ROS‐dependent pathways, with implications for novel combined treatment in gastric cancer |
| title_full | Platinum drugs upregulate CXCR4 and PD‐L1 expression via ROS‐dependent pathways, with implications for novel combined treatment in gastric cancer |
| title_fullStr | Platinum drugs upregulate CXCR4 and PD‐L1 expression via ROS‐dependent pathways, with implications for novel combined treatment in gastric cancer |
| title_full_unstemmed | Platinum drugs upregulate CXCR4 and PD‐L1 expression via ROS‐dependent pathways, with implications for novel combined treatment in gastric cancer |
| title_short | Platinum drugs upregulate CXCR4 and PD‐L1 expression via ROS‐dependent pathways, with implications for novel combined treatment in gastric cancer |
| title_sort | platinum drugs upregulate cxcr4 and pd l1 expression via ros dependent pathways with implications for novel combined treatment in gastric cancer |
| topic | CXCR4 PD‐L1 gastric cancer cisplatin treatment strategy |
| url | https://doi.org/10.1002/2056-4538.70015 |
| work_keys_str_mv | AT xiaoyukang platinumdrugsupregulatecxcr4andpdl1expressionviarosdependentpathwayswithimplicationsfornovelcombinedtreatmentingastriccancer AT linzhang platinumdrugsupregulatecxcr4andpdl1expressionviarosdependentpathwayswithimplicationsfornovelcombinedtreatmentingastriccancer AT shushangliu platinumdrugsupregulatecxcr4andpdl1expressionviarosdependentpathwayswithimplicationsfornovelcombinedtreatmentingastriccancer AT feiwang platinumdrugsupregulatecxcr4andpdl1expressionviarosdependentpathwayswithimplicationsfornovelcombinedtreatmentingastriccancer AT haimingliu platinumdrugsupregulatecxcr4andpdl1expressionviarosdependentpathwayswithimplicationsfornovelcombinedtreatmentingastriccancer AT fenlizhou platinumdrugsupregulatecxcr4andpdl1expressionviarosdependentpathwayswithimplicationsfornovelcombinedtreatmentingastriccancer AT feiwu platinumdrugsupregulatecxcr4andpdl1expressionviarosdependentpathwayswithimplicationsfornovelcombinedtreatmentingastriccancer AT haohaozhang platinumdrugsupregulatecxcr4andpdl1expressionviarosdependentpathwayswithimplicationsfornovelcombinedtreatmentingastriccancer AT daimingfan platinumdrugsupregulatecxcr4andpdl1expressionviarosdependentpathwayswithimplicationsfornovelcombinedtreatmentingastriccancer AT yongzhannie platinumdrugsupregulatecxcr4andpdl1expressionviarosdependentpathwayswithimplicationsfornovelcombinedtreatmentingastriccancer AT zhangqianchen platinumdrugsupregulatecxcr4andpdl1expressionviarosdependentpathwayswithimplicationsfornovelcombinedtreatmentingastriccancer |