The SIX1/LDHA Axis Promotes Lactate Accumulation and Leads to NK Cell Dysfunction in Pancreatic Cancer
Background. Pancreatic cancer (PC) is a malignant cancer with poor prognosis and high mortality rate. Sine oculis homeobox homolog 1 (SIX1) participates in the development of many cancers. However, the function of SIX1 in PC is not fully understood. Methods. SIX1 expression was determined using immu...
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| Format: | Article |
| Language: | English |
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Wiley
2023-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2023/6891636 |
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| author | Wanli Ge Lingdong Meng Shouji Cao Chaoqun Hou Xiaole Zhu Dongya Huang Qiang Li Yunpeng Peng Kuirong Jiang |
| author_facet | Wanli Ge Lingdong Meng Shouji Cao Chaoqun Hou Xiaole Zhu Dongya Huang Qiang Li Yunpeng Peng Kuirong Jiang |
| author_sort | Wanli Ge |
| collection | DOAJ |
| description | Background. Pancreatic cancer (PC) is a malignant cancer with poor prognosis and high mortality rate. Sine oculis homeobox homolog 1 (SIX1) participates in the development of many cancers. However, the function of SIX1 in PC is not fully understood. Methods. SIX1 expression was determined using immunohistochemistry in PC tissues and cell lines. Glucose consumption, lactate production, and ATP assays were used to detect the function of SIX1. PC cells and NK cells were cocultured to study the effect of SIX1 overexpression in PC cells on NK cell function. Chromatin immunoprecipitation (ChIP) assays were used to study the relationship between SIX1 and lactate dehydrogenase A (LDHA). A series of in vitro and in vivo assays were further applied to elucidate the important role of the SIX1/LDHA axis in metabolism and NK cell dysfunction in PC. Results. SIX1 was significantly upregulated in PC tissue; SIX1 overexpression promoted the glycolysis capacity of PANC-1 and CFPAC-1 cells and resulted in NK cell dysfunction after the NK cells had been cultured with PC cells. LDHA inhibitor partially restored the promotion of PC caused by SIX1 overexpression. According to ChIP assays, SIX1 directly binds to the LDHA promoter region. Moreover, LDHA inhibitor and lactate transporter blocker treatment promoted the function of NK cells cocultured with PC cells. In vivo experiments yielded the same results. Conclusion. The SIX1/LDHA axis promotes lactate accumulation and leads to NK cell dysfunction in PC. |
| format | Article |
| id | doaj-art-c9de1948ee5645eebe30c0df6afe0e99 |
| institution | Kabale University |
| issn | 2314-7156 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-c9de1948ee5645eebe30c0df6afe0e992025-02-03T06:42:39ZengWileyJournal of Immunology Research2314-71562023-01-01202310.1155/2023/6891636The SIX1/LDHA Axis Promotes Lactate Accumulation and Leads to NK Cell Dysfunction in Pancreatic CancerWanli Ge0Lingdong Meng1Shouji Cao2Chaoqun Hou3Xiaole Zhu4Dongya Huang5Qiang Li6Yunpeng Peng7Kuirong Jiang8Pancreas CenterPancreas CenterNanjing Medical UniversityPancreas CenterPancreas CenterPancreas CenterPancreas CenterPancreas CenterPancreas CenterBackground. Pancreatic cancer (PC) is a malignant cancer with poor prognosis and high mortality rate. Sine oculis homeobox homolog 1 (SIX1) participates in the development of many cancers. However, the function of SIX1 in PC is not fully understood. Methods. SIX1 expression was determined using immunohistochemistry in PC tissues and cell lines. Glucose consumption, lactate production, and ATP assays were used to detect the function of SIX1. PC cells and NK cells were cocultured to study the effect of SIX1 overexpression in PC cells on NK cell function. Chromatin immunoprecipitation (ChIP) assays were used to study the relationship between SIX1 and lactate dehydrogenase A (LDHA). A series of in vitro and in vivo assays were further applied to elucidate the important role of the SIX1/LDHA axis in metabolism and NK cell dysfunction in PC. Results. SIX1 was significantly upregulated in PC tissue; SIX1 overexpression promoted the glycolysis capacity of PANC-1 and CFPAC-1 cells and resulted in NK cell dysfunction after the NK cells had been cultured with PC cells. LDHA inhibitor partially restored the promotion of PC caused by SIX1 overexpression. According to ChIP assays, SIX1 directly binds to the LDHA promoter region. Moreover, LDHA inhibitor and lactate transporter blocker treatment promoted the function of NK cells cocultured with PC cells. In vivo experiments yielded the same results. Conclusion. The SIX1/LDHA axis promotes lactate accumulation and leads to NK cell dysfunction in PC.http://dx.doi.org/10.1155/2023/6891636 |
| spellingShingle | Wanli Ge Lingdong Meng Shouji Cao Chaoqun Hou Xiaole Zhu Dongya Huang Qiang Li Yunpeng Peng Kuirong Jiang The SIX1/LDHA Axis Promotes Lactate Accumulation and Leads to NK Cell Dysfunction in Pancreatic Cancer Journal of Immunology Research |
| title | The SIX1/LDHA Axis Promotes Lactate Accumulation and Leads to NK Cell Dysfunction in Pancreatic Cancer |
| title_full | The SIX1/LDHA Axis Promotes Lactate Accumulation and Leads to NK Cell Dysfunction in Pancreatic Cancer |
| title_fullStr | The SIX1/LDHA Axis Promotes Lactate Accumulation and Leads to NK Cell Dysfunction in Pancreatic Cancer |
| title_full_unstemmed | The SIX1/LDHA Axis Promotes Lactate Accumulation and Leads to NK Cell Dysfunction in Pancreatic Cancer |
| title_short | The SIX1/LDHA Axis Promotes Lactate Accumulation and Leads to NK Cell Dysfunction in Pancreatic Cancer |
| title_sort | six1 ldha axis promotes lactate accumulation and leads to nk cell dysfunction in pancreatic cancer |
| url | http://dx.doi.org/10.1155/2023/6891636 |
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