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Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway
The most frequent genetic alterations of the TP53 gene in human cancer were reported. TP53 mutation gains new function as a target of genetic instability, which is associated with increased tumor progression and poor survival rate in patients. In this study, more than three hundred colorectal cancer...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990467/ https://www.ncbi.nlm.nih.gov/pubmed/35414774 http://dx.doi.org/10.7150/ijbs.67200 |
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author | Liu, Nannan Jiang, Xinxiu Guo, Leiming Zhang, Chuchu Jiang, Meimei Sun, Zhuoran Zhang, Yizheng Mi, Wunan Li, Jiehan Fu, Yang Wang, Feng Zhang, Lingling Zhang, Yingjie |
author_facet | Liu, Nannan Jiang, Xinxiu Guo, Leiming Zhang, Chuchu Jiang, Meimei Sun, Zhuoran Zhang, Yizheng Mi, Wunan Li, Jiehan Fu, Yang Wang, Feng Zhang, Lingling Zhang, Yingjie |
author_sort | Liu, Nannan |
collection | PubMed |
description | The most frequent genetic alterations of the TP53 gene in human cancer were reported. TP53 mutation gains new function as a target of genetic instability, which is associated with increased tumor progression and poor survival rate in patients. In this study, more than three hundred colorectal cancer patients' samples were firstly analyzed, and the results showed that patients with mutant p53 had higher levels of AKT phosphorylation and PD-L1 expression, which were next verified both in cell lines in vitro and patients' samples in vivo. Further studies demonstrated that the hotspot of mutant p53 directly binds to the promoter of PHLPP2 to inhibit its transcription, and resulting in down-regulating its protein expressional level. Subsequently, AKT was released and activated, promoting tumor proliferation and metastasis. In parallel, 4EBP1/eIF4E was identified as downstream executors of AKT to enhance the translational level of PD-L1, which decreased the activation of T cells. Besides, inhibiting AKT/mTOR pathway significantly suppressed PD-L1 expression, tumor growth, and immune escape in p53 mutated cells. In conclusion, mutant p53 achieved its Gain-of-Function by transcriptionally inhibiting PHLPP2 and activating AKT, which suppresses immune response and advances tumor growth. Thus, this study provides an excellent basis for a further understanding of the clinical treatment of neoplastic diseases for patients with mutant p53, with an emphasis on immunotherapy. |
format | Online Article Text |
id | pubmed-8990467 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-89904672022-04-11 Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway Liu, Nannan Jiang, Xinxiu Guo, Leiming Zhang, Chuchu Jiang, Meimei Sun, Zhuoran Zhang, Yizheng Mi, Wunan Li, Jiehan Fu, Yang Wang, Feng Zhang, Lingling Zhang, Yingjie Int J Biol Sci Research Paper The most frequent genetic alterations of the TP53 gene in human cancer were reported. TP53 mutation gains new function as a target of genetic instability, which is associated with increased tumor progression and poor survival rate in patients. In this study, more than three hundred colorectal cancer patients' samples were firstly analyzed, and the results showed that patients with mutant p53 had higher levels of AKT phosphorylation and PD-L1 expression, which were next verified both in cell lines in vitro and patients' samples in vivo. Further studies demonstrated that the hotspot of mutant p53 directly binds to the promoter of PHLPP2 to inhibit its transcription, and resulting in down-regulating its protein expressional level. Subsequently, AKT was released and activated, promoting tumor proliferation and metastasis. In parallel, 4EBP1/eIF4E was identified as downstream executors of AKT to enhance the translational level of PD-L1, which decreased the activation of T cells. Besides, inhibiting AKT/mTOR pathway significantly suppressed PD-L1 expression, tumor growth, and immune escape in p53 mutated cells. In conclusion, mutant p53 achieved its Gain-of-Function by transcriptionally inhibiting PHLPP2 and activating AKT, which suppresses immune response and advances tumor growth. Thus, this study provides an excellent basis for a further understanding of the clinical treatment of neoplastic diseases for patients with mutant p53, with an emphasis on immunotherapy. Ivyspring International Publisher 2022-03-14 /pmc/articles/PMC8990467/ /pubmed/35414774 http://dx.doi.org/10.7150/ijbs.67200 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Liu, Nannan Jiang, Xinxiu Guo, Leiming Zhang, Chuchu Jiang, Meimei Sun, Zhuoran Zhang, Yizheng Mi, Wunan Li, Jiehan Fu, Yang Wang, Feng Zhang, Lingling Zhang, Yingjie Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway |
title | Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway |
title_full | Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway |
title_fullStr | Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway |
title_full_unstemmed | Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway |
title_short | Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway |
title_sort | mutant p53 achieved gain-of-function by promoting tumor growth and immune escape through phlpp2/akt/pd-l1 pathway |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990467/ https://www.ncbi.nlm.nih.gov/pubmed/35414774 http://dx.doi.org/10.7150/ijbs.67200 |
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