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BMC Cell Biol. 2018 Aug 20;19(1):16. doi: 10.1186/s12860-018-0167-y.

Mutant TP53 G245C and R273H promote cellular malignancy in esophageal squamous cell carcinoma.

Author information

1
State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, National Cancer Center/Cancer Hospital, Beijing, 100021, China.
2
Department of Pathology, Peking University People's Hospital, Beijing, 100044, China.
3
Laboratory of Molecular Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
4
State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, National Cancer Center/Cancer Hospital, Beijing, 100021, China. eileenld@gmail.com.
5
State Key Laboratory of Molecular Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College, National Cancer Center/Cancer Hospital, Beijing, 100021, China. qiminzhan@vip.163.com.
6
Laboratory of Molecular Oncology, Peking University Cancer Hospital and Institute, Beijing, China. qiminzhan@vip.163.com.

Abstract

BACKGROUND:

TP53 gene mutations occur in more than 50% of human cancers and the vast majority of these mutations in human cancers are missense mutations, which broadly occur in DNA binding domain (DBD) (Amino acids 102-292) and mainly reside in six "hotspot" residues. TP53 G245C and R273H point mutations are two of the most frequent mutations in tumors and have been verified in several different cancers. In the previous study of the whole genome sequencing (WGS), we found some mutations of TP53 DBD in esophageal squamous cell carcinoma (ESCC) clinical samples. We focused on two high-frequent mutations TP53 p.G245C and TP53 p.R273H and investigated their oncogenic roles in ESCC cell lines, p53-defective cell lines H1299 and HCT116 p53-/-.

RESULTS:

MTS and colony formation assays showed that mutant TP53 G245C and R273H increased cell vitality and proliferation. Flow cytometry results revealed inhibition of ultraviolet radiation (UV)- and ionizing radiation (IR)- induced apoptosis and disruption of TP53-mediated cell cycle arrest after UV, IR and Nocodazole treatment. Transwell assays indicated that mutant TP53 G245C and R273H enhanced cell migration and invasion abilities. Moreover, western blot revealed that they were able to suppress the expression of TP53 downstream genes in the process of apoptosis and cell cycle arrest induced by UV, which suggests that these two mutations can influence apoptosis and growth arrest might be due, at least in part, to down-regulate the expression of P21, GADD45α and PARP.

CONCLUSIONS:

These results indicate that mutant TP53 G245C and R273H can lead to more aggressive phenotypes and enhance cancer cell malignancy, which further uncover TP53 function in carcinogenesis and might be useful in clinical diagnosis and therapy of TP53 mutant cancers.

KEYWORDS:

Apoptosis; Cell cycle arrest; Cell malignancy; Downstream gene; Esophageal squamous cell carcinoma; Invasion; Migration; TP53 mutation

PMID:
30126368
PMCID:
PMC6102840
DOI:
10.1186/s12860-018-0167-y
[Indexed for MEDLINE]
Free PMC Article

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