c-Met up-regulates the expression of PD-L1 through MAPK/NF-κBp65 pathway
c-Met up-regulates the expression of PD-L1 through MAPK/NF-κBp65 pathway
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c-Met通过MAPK/NF-κBp65通路上调PD-L1的表达
DOI：
10.1007/s00109-022-02179-2
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发表时间：
2022-02-05
影响因子：
4.7
通讯作者：
Tang, Xiaolong
中科院分区：
文献类型：
--
作者：
Xu, Ruyue;Liu, Xinkuang;Tang, Xiaolong
索拉非尼在肝细胞癌（HCC）治疗过程中获得耐药性，降低了药物的疗效。PD-L1诱导的免疫逃逸效应在很大程度上与肝癌的耐药有关。然而，PD-L1的调控机制尚不清楚。本研究旨在阐明PD-L1的调控机制。在PD-L1高表达的Huh-7SR中发现c-Met异常高表达。此外，c-Met作为PD-L1的上游靶分子，在体内外均能促进HCC的增殖和迁移。我们还发现c-Met激活MAPK信号通路和下游NF-κ Bp 65转录因子，后者与PD-L1启动子近端区域相互作用，促进PD-L1表达。结论：c-Met通过MAPK/NF-κ Bp 65通路调控PD-L1的转录，从而促进HCC的发生发展。c-Met和PD-L1在HCC中的作用还有待进一步研究，但它是HCC治疗的潜在靶点。图形摘要Key messages在研究中发现，c-Met在PD-L1高表达的Huh-7SR中也异常高表达，在体外和体内都能促进HCC的发展。PD-L1与c-Met表达水平呈正相关，在后续机制研究中，我们发现c-Met激活MAPK信号通路，随后激活下游NF-κ Bp 65转录因子，与PD-L1启动子近端区域相互作用，促进PD-L1表达，我们研究发现c-Met通过MAPK/NF-κ Bp 65通路调控PD-L1的转录，从而促进HCC的进展。
Sorafenib acquired drug resistance during the treatment of hepatocellular carcinoma (HCC) reduces the efficacy of the drug. The immune escape effect induced by PD-L1 is largely associated with drug resistance of HCC. However, the regulated mechanism of PD-L1 is unclear. This research aimed to clarify the control mechanism of PD-L1. c-Met was found abnormally highly expressed in Huh-7SRwith high PD-L1 expression. In addition, c-Met, as the upstream target molecule of PD-L1, promoted the proliferation and migration of HCC in vitro and in vivo. We also found that c-Met activated the MAPK signaling pathway and the downstream NF-κBp65 transcription factor, which interacts with the proximal region of the PD-L1 promoter to promote PD-L1 expression. In conclusion, c-Met regulates the transcription of PD-L1 through the MAPK/NF-κBp65 pathway, thereby promoting the progress of HCC. The role of c-Met and PD-L1 in HCC needs to be further studied, but it is a potential target for the treatment of HCC.Graphical abstractKey messagesIn the study, it was found that c-Met is also abnormally highly expressed in Huh-7SRwith high PD-L1 expression and can promote the development of HCC in vitro and in vivo. PD-L1 and c-Met expression levels are positively correlated.In the follow-up mechanism study, we found that c-Met activated the MAPK signaling pathway and subsequently activated the downstream NF-κBp65 transcription factor, which interacts with the proximal region of the PD-L1 promoter to promote PD-L1 expression.Our study found that c-Met regulates the transcription of PD-L1 through the MAPK/NF-κBp65 pathway, thereby promoting the progress of HCC.