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

Abstract

BackgroundTP53 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−/−.ResultsMTS 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (10.1186/s12860-018-0167-y) contains supplementary material, which is available to authorized users.

Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma

“…The biological role of mutant TP53 in this study is consistent with reports of its oncogenic function following gain of function mutations in other cancers. [32][33][34] In a recent study of esophageal squamous cell carcinomas, mutant TP53 G245C and TP53 R273H led to a more aggressive phenotype with an enhanced malignant potential, arising due to increasing cell vitality, and proliferation, enhancing cell migration, and invasion abilities and suppressing the expression of TP53 downstream genes involved in the process of apoptosis and cell cycle arrest. 32 In breast cancers, the TP53 R273H mutation also led to significantly greater cell growth than wild-type TP53.…”

“…[32][33][34] In a recent study of esophageal squamous cell carcinomas, mutant TP53 G245C and TP53 R273H led to a more aggressive phenotype with an enhanced malignant potential, arising due to increasing cell vitality, and proliferation, enhancing cell migration, and invasion abilities and suppressing the expression of TP53 downstream genes involved in the process of apoptosis and cell cycle arrest. 32 In breast cancers, the TP53 R273H mutation also led to significantly greater cell growth than wild-type TP53. 33 In pleomorphic rhabdomyosarcomas, xenograft models expressing mutant TP53 displayed a tumor profile that was more aggressive and with greater metastatic potential than p53 null or p53 wild-type mice.…”

Molecular crosstalk between cancer and neurodegenerative diseases

“…In most of these cases, p53 gene has been reported to contain missense mutations [36][37][38][39]. The mutant p53 proteins no longer have tumor suppressor activity, and obtain several gainof-functions such as invasion [40][41][42][43][44][45][46][47][48], enhanced migration [42,[49][50][51][52], anchorage-independent growth [53][54][55][56][57][58], propagation of cell cycle [59][60][61][62][63][64][65], cell survival and avoidance of cell death [66][67][68][69][70][71][72][73][74][75][76], genomic instability [77][78][79][80][81][82], and angiogenesis…”

The anticancer effects of cinobufagin on hepatocellular carcinoma Huh‑7�cells are associated with activation of the p73 signaling pathway

“…Numerous studies have reported that mutations in various genes can markedly alter the efficacy of chemotherapy, including p53, B-Raf proto-oncogene, serine/threonine kinase and erb-b2 receptor tyrosine kinase 2 (6–9). Mutations in p53 occur frequently in numerous types of malignant tumor (10–12). HCC cells have been reported to express three genotypes of p53: Wild-type p53, mutant p53 and p53-null (13).…”