Abstract
The common understanding of p53 function is a genome guardian, which is activated by diverse stresses stimuli and mediates DNA repair, apoptosis, and cell cycle arrest. Increasing evidence has demonstrated p53 new cellular functions involved in abundant endocrine and metabolic response for maintaining homeostasis. However, TP53 is frequently mutant in human cancers, and the mutant p53 (Mut-p53) turns to an “evil” cancer-assistant. Mut-p53-induced epithelial-mesenchymal transition (EMT) plays a crucial role in the invasion and metastasis of endocrine carcinomas, and Mut-p53 is involved in cancer immune evasion by upregulating PD-L1 expression. Therefore, Mut-p53 is a valuable treatment target for malignant tumors. Targeting Mut-p53 in correcting sequence and conformation are increasingly concerned. Interestingly, in wild animals, p53 variations contribute to cancer resistant and high longevity. This review has discussed the multiple functions of p53 in health, diseases, and nature evolution, summarized the frequently mutant sites of p53, and the mechanisms of Mut-p53-mediated metastasis and immune evasion in endocrine cancers. We have provided a new insight for multiple roles of p53 in human and wild animals.
Highlights
mutant p53 (Mut-p53) Mediates Invasion, Metastasis, and Immune Evasion High invasion and metastatic risk are the fatal hallmark of endocrine adenocarcinomas, such as 60∼80% breast and prostate cancer have developed bone metastasis [58], about 70% pancreatic cancer patients die from extensive metastatic diseases [59]
CRISPR/Cas9 technique already can efficiently relieve disease phenotypes of hereditary tyrosinemia type I (HT-1) in mice by correcting fumarylacetoacetate hydrolase (FAH) mutation [88]. These findings suggested that CRISPR/Cas9 could correct Mut-p53 sequence by replacing with a wildtype p53 (Wt-p53) functional copy, which is possible to be utilized in clinical research
As a cellular sensor for homeostasis, p53 involves in metabolism, autophagy regulation, insulin resistance or secretion, and food intake
Summary
Mut-p53 Mediates Invasion, Metastasis, and Immune Evasion High invasion and metastatic risk are the fatal hallmark of endocrine adenocarcinomas, such as 60∼80% breast and prostate cancer have developed bone metastasis [58], about 70% pancreatic cancer patients die from extensive metastatic diseases [59]. This review summarized the pivotal molecular pathways and inhibitors in Mut-p53-mediated EMT/non-EMT process related invasion and metastasis (Figure 2). In pancreatic cancer mouse model (KPC model, LSL-KrasG12D; P53R172H/+; Pdx1-cre), PDGFRβ is upregulated and induces tumor metastasis by Mut-p53-mediated p73/NF-Y complex disruption [62].
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