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Alpha-fetoprotein upregulates hepatocellular carcinoma cell-intrinsic PD-1 expression through the LATS2/YAP/TEAD1
Guangxian Leng1, Hongxia Gong2, Guiyuan Liu3
1Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, Gansu Province, China.
Background:
Hepatocellular carcinoma (HCC) cell-intrinsic programmed death 1 (PD-1) promotes tumor progression. However, the mechanisms that regulate its expression are unclear. This study investigated the impact of alpha-fetoprotein (AFP) on HCC cell-intrinsic PD-1 expression.
Methods:
The expression of PD-1 and AFP at the gene and protein levels was detected using real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB). Proteins interacting with AFP were examined by co-immunoprecipitation (CO-IP). Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were used to identify transcription-enhanced association domain 1 (TEAD1) binding to the promoter of PD-1.
Results:
The expression of HCC cell-intrinsic PD-1 was positively correlated with AFP. Mechanistically, AFP inhibited the phosphorylation of large tumor suppressor 2 (LATS2) and yes-associated protein (YAP). As a result, YAP is transferred to the nucleus and forms a transcriptional complex with TEAD1, promoting PD-1 transcription by binding to its promoter.
Conclusion:
AFP is an upstream regulator of the HCC cell-intrinsic PD-1 and increases PD-1 expression via the LATS2/YAP/TEAD1 axis.
General:
Our findings provide insight into the mechanisms of HCC development and offer new ideas for further in-depth studies of HCC.
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