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Establishment and Characterization of a New Immortalized Human Oral Keratinocyte (HOK) Cell Line Harboring Various TP53 Mutations

ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is characterized by frequent TP53 mutations, which include gain-of-function (GOF) variants that drive tumor progression and chemoresistance. While genomic evidence across multiple invasive and metastatic specimens indicates TP53 loss or mutation occurs relatively early in HNSCC carcinogenesis, it has been difficult to discern how TP53 mutation drives further tumor evolution and influences the tumor microenvironment. To address this question, we generated an immortalized human oral keratinocyte (HOK) cell line expressing various TP53 mutant forms to determine how mutations impact functional and genomic characteristics of HOKs that can in turn drive their evolution to neoplastic cells. Key results revealed significant phenotypic and molecular divergence: high-risk lines exhibited enhanced invasiveness and chemoresistance compared to low-risk counterparts. Weighted gene co-expression network analysis (WGCNA) linked high-risk mutations to pro-metastatic pathways and stress-response signatures, with the C238F line uniquely enriched for p53-related GOF mechanisms.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305620 | GEO | 2026/05/06

REPOSITORIES: GEO

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Project description:Background: Although TP53 gain-of-function (GOF) mutations promote cancer survival, its effect on EGFR-TKI efficacy remains unclear. We established EGFR-mutant lung cancer cell lines expressing various TP53 genotypes using CRISPR-Cas9 technology and found that TP53-GOF mutant cells develop an early resistance to EGFR-TKI osimertinib.The goal of this study is to elucidate the mechanisms underlying resistance to osimertinib treatment in TP53 GOF mutations through comprehensive gene analysis using RNA-seq with next-generation sequencing (NGS). Methods: Total RNA was isolated from PC-9 cells overexpressing TP53 R248Q mutation (PC9/p53R248Q: TP53 GOF mutation) and PC-9 cells overexpressing empty vector plasmid (PC9/p53EV: TP53 null) treated with DMSO or osimertinib for 24hours, using the RNeasy Micro Kit , in accordance with the manufacturer’s instructions. RNA samples were quantified by NanoDrop-2000 spectrophotometer, and the quality was confirmed with a 2200 TapeStation. rRNA was removed using MGI Easy rRNA Depletion Kit according to manufacturer's instructions followed by library construction using MGIEasy RNA Directional Library Prep Set (MGI). MGI DNBseq-G400 FAST was used to perform the amplicons deep sequencing following the standard operation protocol. The sequence format was 150bp pair read for all samples. All sequencing reads were trimmed low-quality bases and adapters with Trimmomatic (v.0.38) , and RNA sequencing reads were mapped to hg38 using HISAT2 software . Raw counts for each gene were estimated in each sample using RSEM version 1.3.0 and Bowtie 2. Calculation of the log fold-change (log FC) and p-value were performed using edgeR. Results: We explored the functions of specifically upregulated genes in TP53 GOF mutation after osimertinib treatment by KEGG pathway-enrichment analysis and found that the cytokine-cytokine receptor interaction was the most significantly altered pathway. Hallmark pathway analysis identified the TNF-α/NF-κB pathway was significantly enriched. Furthermore, TRRUST analysis showed enhanced activity of transcription factors especially RELA (p65) and NF-kB1. Conclusions: TP53 GOF mutaion induces osimertinib resistance by activating TNF-α/NF-κB pathway.

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Establishment and Characterization of a New Immortalized Human Oral Keratinocyte (HOK) Cell Line Harboring Various TP53 Mutations

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