{"title":"The SIX1/LDHA Axis Promotes Lactate Accumulation and Leads to NK Cell Dysfunction in Pancreatic Cancer.","authors":"Wanli Ge, Lingdong Meng, Shouji Cao, Chaoqun Hou, Xiaole Zhu, Dongya Huang, Qiang Li, Yunpeng Peng, Kuirong Jiang","doi":"10.1155/2023/6891636","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>The SIX1/LDHA axis promotes lactate accumulation and leads to NK cell dysfunction in PC.</p>","PeriodicalId":15952,"journal":{"name":"Journal of Immunology Research","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2023-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10022590/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Immunology Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1155/2023/6891636","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
背景:胰腺癌(PC)是一种预后差、死亡率高的恶性肿瘤:胰腺癌(PC)是一种预后差、死亡率高的恶性肿瘤。Sine oculis homeobox homolog 1(SIX1)参与了许多癌症的发展。然而,SIX1 在 PC 中的功能尚不完全清楚:方法:采用免疫组化方法测定 SIX1 在 PC 组织和细胞系中的表达。葡萄糖消耗、乳酸生成和 ATP 试验用于检测 SIX1 的功能。PC 细胞与 NK 细胞共培养,研究 PC 细胞中 SIX1 的过表达对 NK 细胞功能的影响。染色质免疫沉淀(ChIP)测定用于研究 SIX1 与乳酸脱氢酶 A(LDHA)之间的关系。通过一系列体外和体内试验,进一步阐明了SIX1/LDHA轴在PC代谢和NK细胞功能障碍中的重要作用:结果:SIX1在PC组织中明显上调;SIX1过表达促进了PANC-1和CFPAC-1细胞的糖酵解能力,并在NK细胞与PC细胞培养后导致NK细胞功能障碍。LDHA 抑制剂部分恢复了 SIX1 过表达对 PC 的促进作用。根据 ChIP 检测,SIX1 直接与 LDHA 启动子区域结合。此外,LDHA 抑制剂和乳酸转运体阻断剂能促进与 PC 细胞共培养的 NK 细胞的功能。体内实验也得出了相同的结果:结论:SIX1/LDHA轴促进乳酸积累并导致PC中NK细胞功能障碍。
期刊介绍:
Journal of Immunology Research is a peer-reviewed, Open Access journal that provides a platform for scientists and clinicians working in different areas of immunology and therapy. The journal publishes research articles, review articles, as well as clinical studies related to classical immunology, molecular immunology, clinical immunology, cancer immunology, transplantation immunology, immune pathology, immunodeficiency, autoimmune diseases, immune disorders, and immunotherapy.