P53 In Esophageal Squamous Cell Carcinoma Research Articles

Mutant p53 activates hnRNPA2B1-AGAP1-mediated exosome formation to promote esophageal squamous cell carcinoma progression

p53 mutations predispose cancer cell development, promote their survival and metastasis, and lead to ineffective therapeutic responses and unfavorable prognosis. No drug that abrogates the oncogenic functions of mutant p53 has been approved for cancer treatment. Here, we performed whole-genome sequencing of 663 esophageal squamous cell carcinoma (ESCC) tumor tissues and paired normal tissues. The results indicated that ESCC samples from our cohort had a more dispersed distribution of TP53 mutants and a higher proportion of nonsense mutants than European and American ESCC samples in the International Agency for Research on Cancer (IARC) database. The most frequent p53 mutations disrupt the inhibition of proliferation, migration, and invasion mediated by wild-type p53 in ESCC. Furthermore, p53 mutations alter its protein nucleoplasmic localization and protein stability. The p53 mutation G245S (p53-G245S) interacts with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) to increase protein translation of phosphatidylinositol-dependent Arf GAP (AGAP1) by promoting AGAP1 mRNA stability. AGAP1 promotes cancer cell proliferation and metastasis by enhancing exosome formation. Furthermore, we explored the combination of the HSP90 inhibitor HSP90i and the AGAP1 inhibitor QS11 could inhibit ESCC cell proliferation and metastasis. Thus, the p53-G245S/hnRNPA2B1/AGAP1 axis promotes ESCC progression by enhancing exosome formation, and the combination of an HSP90 inhibitor and an AGAP1 inhibitor may serve as a potential therapeutic strategy.

P53 codon 72 polymorphism, loss of heterozygosity and high-risk human papillomavirus infection in a low-incidence German esophageal squamous cell carcinoma patient cohort

Epidemiological studies in endemic geographic regions for esophageal squamous cell carcinoma (ESCC) suggested a number of risk factors, including modifications of the p53 tumor suppressor by codon Arg72Pro polymorphism, loss of heterozygosity (LOH) or human papillomavirus type 16 or 18 (HPV 16/18) infection. The p53 Arg72 variant has been suggested to be a high-risk factor in HPV-associated tumors. The present study analysed these associations in a low incidence geographic region in Germany. Fifty-three paraffin-embedded tumors and 53 surrounding normal squamous epithelium were investigated. For detection of p53 codon Arg72Pro polymorphism, direct sequencing for exon 4 was conducted. LOH analysis was performed using three microsatellite markers at the p53 gene locus, and all cases were screened for high-risk HPV infection (HPV 16 and 18) with primer specific PCR and confirmed by sequencing. The p53 codon 72 genotype distribution was identical to published studies of normal Caucasian population, suggesting no general influence of this polymorphism on esophageal cancer risk in Germany. One case showed a p53 mutation in exon 4. p53 LOH was found in 13/44 (30%) informative cases without any correlation to histopathological characteristics. Of 53 (17%) samples, 9 showed HPV 16 or 18 infection. We found no association between p53 codon 72 genotypes and increasing HPV infection rates. Interestingly, 8/9 HPV-positive cases showed at least one p53 Arg72 allele. These results indicate an important role of p53 in ESCC also in low-incidence regions. In combination with the p53 Arg72 variant HPV infection could contribute to the risk of ESCC development in these cases, as has been demonstrated for high-risk regions.