Heterozygous p53-R280T Mutation Enhances the Oncogenicity of NPC Cells Through Activating PI3K-Akt Signaling Pathway

Abstract

A heterozygous point mutation of p53 gene at codon 280 from AGA to ACA (R280T) frequently occurs in nasopharyngeal carcinoma (NPC) cell lines, and about 10% NPC tissues. However, the role of this mutation in the pathogenesis of NPC remains unclear. In this study, we generated p53 knockout (KO) NPC cell lines from CNE2 cells carrying heterozygous p53 R280T (p53-R280T) mutation and C666-1 cells carrying wild-type p53 by CRISPR-Cas9 gene editing system, and found that KO of heterozygous p53-R280T significantly decreased NPC cell proliferation and increased NPC cell apoptosis, whereas KO of wild-type p53 had opposite effects on NPC cell proliferation and apoptosis. Moreover, KO of heterozygous p53-R280T inhibited the anchorage-independent growth and in vivo tumorigenicity of NPC cells. mRNA sequencing of heterozygous p53-R280T KO and control CNE2 cells revealed that heterozygous p53-R280T mutation activated PI3K-Akt signaling pathway. Moreover, blocking of PI3K-Akt signaling pathway abolished heterozygous p53-R280T mutation-promoting NPC cell proliferation and survival. Our data indicate that p53 with heterozygous R280T mutation functions as an oncogene, and promotes the oncogenicity of NPC cells by activating PI3K-Akt signaling pathway.

NPC-Exosome Carry Wild and Mutant-type p53 among Nasopharyngeal Cancer Patients

“…(13) In exon 8, there can be mutations at codon 280 from AGA to ACA in NPC cell lines that can increase NPC oncogenicity. (22) Mutant p53 was associated with the poor prognosis in colon cancer. This condition was related to macrophage reprogramming through the exosomal miR-1246.…”

Identifying 8-mRNAsi Based Signature for Predicting Survival in Patients With Head and Neck Squamous Cell Carcinoma via Machine Learning

“…KEGG enrichment pathways in the yellow module were mainly involved in ECM–receptor interactions, PI3K-Akt signaling pathways, and MAPK signaling pathways. These signaling pathways have been demonstrated to facilitate cell survival, self-renewal and apoptosis inhibition in many CSCs ( Huang et al, 2017 ; Chen et al, 2020 ; Liao et al, 2020 ; Qin et al, 2020 ).…”

Small biomarkers with massive impacts: PI3K/AKT/mTOR signalling and microRNA crosstalk regulate nasopharyngeal carcinoma

“…This signalling pathway can be activated by a variety of cellular stimuli, such as low levels of nutrients and/or oxygen supply, ionizing radiation, and pH [ 21 ]. Aberrant activation of PI3K signalling is frequently reported in aggressive tumours, such as NPC [ 25 ]. PI3Ks are lipid kinases that are divided into three different classes, including class I PI3Ks, class II PI3Ks, and class III PI3Ks [ 26 ].…”