The EGFR-P38 MAPK axis up-regulates PD-L1 through miR-675-5p and down-regulates HLA-ABC via hexokinase-2 in hepatocellular carcinoma cells.
The EGFR-P38 MAPK axis up-regulates PD-L1 through miR-675-5p and down-regulates HLA-ABC via hexokinase-2 in hepatocellular carcinoma cells.
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肝细胞癌细胞中 EGFR-P38 MAPK 轴通过 miR-675-5p 上调 PD-L1，并通过己糖激酶-2 下调 HLA-ABC
DOI：
10.1002/cac2.12117
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Liu L
中科院分区：
文献类型：
--
作者：
Liu Z;Ning F;Cai Y;Sheng H;Zheng R;Yin X;Lu Z;Su L;Chen X;Zeng C;Wang H;Liu L
免疫疗法已被证明是一种有前途的策略，对人类癌症。深入了解肝癌的免疫调节机制有助于肝癌免疫治疗的发展。表皮生长因子受体（EGFR）信号在肝细胞癌中被频繁激活，并在肿瘤发生中起重要作用。然而，其在HCC免疫中的作用在很大程度上仍然未知。本研究旨在研究EGFR信号传导对HCC细胞中程序性死亡配体1（PD-L1）和人类白细胞抗原I类（HLA-I）表达的影响及其潜在机制。采用免疫组化法检测HCC标本中磷酸化EGFR（p-EGFR）、PD-L1和HLA-I（HLA-ABC）的表达，并分析其相关性。通过定量真实的时间PCR、蛋白质印迹和流式细胞术检测EGFR激活的HCC细胞中的PD-L1和HLA-ABC表达，并进行T细胞介导的裂解以测试HCC细胞中PD-L1和HLA-ABC改变的免疫抑制作用。此外，通过动物实验、荧光素酶报告基因测定和基因获得和功能丧失研究探索了EGFR活化诱导的PD-L1上调和HLA-ABC下调的潜在机制。p-EGFR与PD-L1呈正相关，与HLA-ABC表达呈负相关。EGFR通过其配体EGF的激活上调了HCC细胞中的PD-L1并下调了HLA-ABC，这在功能上是重要的，并且可以被EGFR抑制剂吉非替尼在体外和体内消除。机制上，增强的P38丝裂原活化蛋白激酶（MAPK）激活下调microRNA-675 - 5 p（miR-675 - 5 p）和上调的糖酵解相关酶己糖激酶2（HK 2）; miR-675 - 5 p下调可能通过PD-L1的3 '-非翻译区（3'-UTR）增强PD-L1 mRNA的稳定性，从而导致PD-L1蓄积，和HK 2上调增强有氧糖酵解并介导HLA-ABC的减少。在HCC细胞中，EGFR-P38 MAPK轴可通过miR-675 - 5 p上调PD-L1，并通过HK 2下调HLA-ABC。我们的研究揭示了一种可能导致肝癌免疫抑制的新型信号网络，并表明EGFR信号可以成为肝癌免疫治疗的靶点。
Immunotherapy has been shown to be a promising strategy against human cancers. A better understanding of the immune regulation in hepatocellular carcinoma (HCC) could help the development of immunotherapy against HCC. The epidermal growth factor receptor (EGFR) signaling is frequently activated in HCC and plays important roles in tumorigenesis. However, its role in HCC immunity is still largely unknown. This study aimed to investigate the impact of EGFR signaling on programmed death‐ligand 1 (PD‐L1) and human leukocyte antigen class‐I (HLA‐I) expression in HCC cells and its underlying mechanisms. The expression of phosphorylated EGFR (p‐EGFR), PD‐L1, and HLA‐I (HLA‐ABC) in HCC specimens was detected by immunohistochemistry, and their correlations were analyzed. PD‐L1 and HLA‐ABC expression in EGFR‐activated HCC cells were detected by quantitative real‐time PCR, Western blotting, and flow cytometry, and T cell‐mediated lysis was performed to test the immunosuppressive effects of PD‐L1 and HLA‐ABC alterations in HCC cells. Furthermore, the underlying mechanisms of EGFR activation‐induced PD‐L1 up‐regulation and HLA‐ABC down‐regulation were explored by animal experiments, luciferase reporter assay, and gene gain‐ and loss‐of‐function studies. p‐EGFR was positively correlated with PD‐L1 and negatively correlated with HLA‐ABC expression in HCCs. EGFR activation by its ligand EGF up‐regulated PD‐L1 and down‐regulated HLA‐ABC in HCC cells, which was functionally important and could be abolished by the EGFR inhibitor, gefitinib, both in vitro and in vivo. Mechanistically, enhanced P38 mitogen‐activated protein kinase (MAPK) activation down‐regulated microRNA‐675‐5p (miR‐675‐5p) and up‐regulated glycolysis‐related enzyme hexokinase 2 (HK2); miR‐675‐5p down‐regulation enhanced the stability of PD‐L1 mRNA probably via the 3’‐untranslated region (3’‐UTR) of PD‐L1 and thereby caused PD‐L1 accumulation, and HK2 up‐regulation enhanced aerobic glycolysis and mediated a decrease in HLA‐ABC. The EGFR‐P38 MAPK axis could up‐regulate PD‐L1 through miR‐675‐5p and down‐regulate HLA‐ABC via HK2 in HCC cells. Our study reveals a novel signaling network that may cause immune suppression in HCC and suggests that EGFR signaling can be targeted for HCC immunotherapy.
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影响因子：
3.8
作者：
Luedke, Eric;Jaime-Ramirez, Alena Cristina;Bhave, Neela;Roda, Julie;Choudhary, Moaz Maqbool;Kumar, Bhavna;Teknos, Theodoros N.;Carson, William E., III
通讯作者：
Carson, William E., III
影响因子：
11.2
作者：
Lim SO;Li CW;Xia W;Lee HH;Chang SS;Shen J;Hsu JL;Raftery D;Djukovic D;Gu H;Chang WC;Wang HL;Chen ML;Huo L;Chen CH;Wu Y;Sahin A;Hanash SM;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
影响因子：
29
作者：
Cascone T;McKenzie JA;Mbofung RM;Punt S;Wang Z;Xu C;Williams LJ;Wang Z;Bristow CA;Carugo A;Peoples MD;Li L;Karpinets T;Huang L;Malu S;Creasy C;Leahey SE;Chen J;Chen Y;Pelicano H;Bernatchez C;Gopal YNV;Heffernan TP;Hu J;Wang J;Amaria RN;Garraway LA;Huang P;Yang P;Wistuba II;Woodman SE;Roszik J;Davis RE;Davies MA;Heymach JV;Hwu P;Peng W
通讯作者：
Peng W
表皮生长因子和肿瘤坏死因子α通过NF-kappa B/p65协同诱导纤连蛋白协同促进肝癌细胞系的运动
DOI：
10.1016/j.bbagen.2017.08.010
发表时间：
2017-11-01
影响因子：
3
作者：
Liu, Zong-Cai;Ning, Fen;Du, Jun
通讯作者：
Du, Jun
影响因子：
13.5
作者：
Calderaro, Julien;Rousseau, Benoit;Pawlotsky, Jean-Michel
通讯作者：
Pawlotsky, Jean-Michel