ATXN2-Mediated PI3K/AKT Activation Confers Gastric Cancer Chemoresistance and Attenuates CD8+ T Cell Cytotoxicity
As one of the primary therapeutic choices, chemotherapy is widely adopted for progressive gastric cancer (GC), but the development of chemoresistance has limited chemotherapy efficacy and partly contributes to poor prognosis. Immunotherapy is increasingly being applied in the clinical treatment of G...
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| Format: | Article |
| Language: | English |
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Wiley
2022-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2022/6863240 |
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| author | Qi Wang Tianyu Cao Xiaohui Zhang Juan Hui Chen Wang Wenyao Zhang Pei Wang Yun Zhou Shuang Han |
| author_facet | Qi Wang Tianyu Cao Xiaohui Zhang Juan Hui Chen Wang Wenyao Zhang Pei Wang Yun Zhou Shuang Han |
| author_sort | Qi Wang |
| collection | DOAJ |
| description | As one of the primary therapeutic choices, chemotherapy is widely adopted for progressive gastric cancer (GC), but the development of chemoresistance has limited chemotherapy efficacy and partly contributes to poor prognosis. Immunotherapy is increasingly being applied in the clinical treatment of GC and is also benefitting patients. To ascertain whether ATXN2 affects chemotherapy efficacy in GC cells and its role in GC immune escape, we performed high-throughput sequencing to clarify genes differentially expressed between 5-FU-resistant and 5-FU-sensitive GC cells and then conducted qRT–PCR to assess ATXN2 expression in GC tissues. Furthermore, the influence of ATXN2 on resistance was studied in vitro and in vivo, ATXN2 and other protein expression levels were detected using Western blotting and immunohistochemistry (IHC), and the direct association of SP1 and ATXN2 was confirmed through luciferase reporter gene analysis. We found elevated ATXN2 in GC tumors and a negative correlation between ATXN2 levels and the prognosis of GC. Furthermore, by activating the PI3K/AKT pathway, ATXN2 was found to promote chemoresistance in GC, facilitating BCL2L1 expression. In GC cells, ATXN2 further stimulated PD-L1 expression and provided better immunotherapy efficacy. Finally, we demonstrated that SP1 transcriptionally regulated the expression of ATXN2 and prompted GC chemoresistance and immune escape. In conclusion, our study reveals the important roles of the SP1/ATXN2/PI3K-AKT/BCL2L1 signalling pathway in GC chemoresistance and of the SP1/ATXN2/PI3K-AKT/PD-L1 signalling pathway in GC immunotherapy. Our findings provide new theories and experimental references for overcoming chemotherapy resistance in GC and enhancing the efficacy of immunotherapy for GC. |
| format | Article |
| id | doaj-art-e810a53551df4a3982200ec758e4f9f1 |
| institution | OA Journals |
| issn | 2314-7156 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-e810a53551df4a3982200ec758e4f9f12025-08-20T02:21:39ZengWileyJournal of Immunology Research2314-71562022-01-01202210.1155/2022/6863240ATXN2-Mediated PI3K/AKT Activation Confers Gastric Cancer Chemoresistance and Attenuates CD8+ T Cell CytotoxicityQi Wang0Tianyu Cao1Xiaohui Zhang2Juan Hui3Chen Wang4Wenyao Zhang5Pei Wang6Yun Zhou7Shuang Han8Honghui HospitalThe 928 Hospital of PLA Joint Logistics Support ForcesState Key Laboratory of Cancer BiologyDepartment of GastroenterologyDepartment of GastroenterologyState Key Laboratory of Cancer BiologyDepartment of GastroenterologyDepartment of GastroenterologyHonghui HospitalAs one of the primary therapeutic choices, chemotherapy is widely adopted for progressive gastric cancer (GC), but the development of chemoresistance has limited chemotherapy efficacy and partly contributes to poor prognosis. Immunotherapy is increasingly being applied in the clinical treatment of GC and is also benefitting patients. To ascertain whether ATXN2 affects chemotherapy efficacy in GC cells and its role in GC immune escape, we performed high-throughput sequencing to clarify genes differentially expressed between 5-FU-resistant and 5-FU-sensitive GC cells and then conducted qRT–PCR to assess ATXN2 expression in GC tissues. Furthermore, the influence of ATXN2 on resistance was studied in vitro and in vivo, ATXN2 and other protein expression levels were detected using Western blotting and immunohistochemistry (IHC), and the direct association of SP1 and ATXN2 was confirmed through luciferase reporter gene analysis. We found elevated ATXN2 in GC tumors and a negative correlation between ATXN2 levels and the prognosis of GC. Furthermore, by activating the PI3K/AKT pathway, ATXN2 was found to promote chemoresistance in GC, facilitating BCL2L1 expression. In GC cells, ATXN2 further stimulated PD-L1 expression and provided better immunotherapy efficacy. Finally, we demonstrated that SP1 transcriptionally regulated the expression of ATXN2 and prompted GC chemoresistance and immune escape. In conclusion, our study reveals the important roles of the SP1/ATXN2/PI3K-AKT/BCL2L1 signalling pathway in GC chemoresistance and of the SP1/ATXN2/PI3K-AKT/PD-L1 signalling pathway in GC immunotherapy. Our findings provide new theories and experimental references for overcoming chemotherapy resistance in GC and enhancing the efficacy of immunotherapy for GC.http://dx.doi.org/10.1155/2022/6863240 |
| spellingShingle | Qi Wang Tianyu Cao Xiaohui Zhang Juan Hui Chen Wang Wenyao Zhang Pei Wang Yun Zhou Shuang Han ATXN2-Mediated PI3K/AKT Activation Confers Gastric Cancer Chemoresistance and Attenuates CD8+ T Cell Cytotoxicity Journal of Immunology Research |
| title | ATXN2-Mediated PI3K/AKT Activation Confers Gastric Cancer Chemoresistance and Attenuates CD8+ T Cell Cytotoxicity |
| title_full | ATXN2-Mediated PI3K/AKT Activation Confers Gastric Cancer Chemoresistance and Attenuates CD8+ T Cell Cytotoxicity |
| title_fullStr | ATXN2-Mediated PI3K/AKT Activation Confers Gastric Cancer Chemoresistance and Attenuates CD8+ T Cell Cytotoxicity |
| title_full_unstemmed | ATXN2-Mediated PI3K/AKT Activation Confers Gastric Cancer Chemoresistance and Attenuates CD8+ T Cell Cytotoxicity |
| title_short | ATXN2-Mediated PI3K/AKT Activation Confers Gastric Cancer Chemoresistance and Attenuates CD8+ T Cell Cytotoxicity |
| title_sort | atxn2 mediated pi3k akt activation confers gastric cancer chemoresistance and attenuates cd8 t cell cytotoxicity |
| url | http://dx.doi.org/10.1155/2022/6863240 |
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