Attenuation of aggressive tumor progression of anaplastic thyroid cancer by p53
Related Experiment Video
Updated: Jun 10, 2025
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
Eunmi Hwang1, Michael Kruhlak2, Nathan Wong3,4
1Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892, USA.
Abstract:
Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer, with very limited treatment options. Mutations of p53 are associated with lethal outcomes of ATC. In this study, we tested the hypothesis that wild type p53 (WTp53) mitigates its aggressive progression. We used human 8505C cells (from human ATC tumors) as a model, harboring a BRAFV600E mutation and single of mutated p53C742G allele. We exogenously expressed WTp53 or mutant p53C742G into 8505C cells (8505C-WTp53 or 8505C-MTp53, respectively). The expressed WTp53 inhibited cell proliferation, decreased cell migration, and induced apoptosis via induction of proapoptotic WTp53 target BAX and PUMA genes in vitro. Mouse xenograft studies showed suppression of tumors induced by 8505C-WTp53 but not by 8505C-MTp53 cells. Consistent with in vitro findings, WTp53 inhibited proliferation of tumor cells, evidenced by decreased proliferation marker Ki-67 in tumors. WTp53 also induced apoptosis in xenograft tumors as shown by increased cleaved caspase-3 proteins and pro-apoptotic regulators, BAX and PUMA. Single cells RNA-sequencing (scRNA-seq) of tumors induced by 8505C, 8505C-WTp53, and 8505C-MTp53 cells demonstrated differential expression gene (DEG) patterns between 8505C-WTp53 and 8505C tumors. DEGs analysis identified alteration of multiple pathways, leading to attenuating the oncogenic actions of mutant p53. The discovery of the suppression of TNFα via NFκB pathway topped the pathways list, resulting in subduing the deleterious inflammatory responses caused by mutant p53. Our findings that exogenously expressed WTp53 could counter act the oncogenic actions of p53 has heightened the feasibility of using CRISPR/Cas9 genome editing to modify the p53 alleles for potential treatment of ATC.
Insights
Wild type p53 (WTp53) significantly inhibits anaplastic thyroid cancer (ATC) progression by reducing cell proliferation and migration. Restoring WTp53 function offers a promising therapeutic strategy for aggressive ATC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Anaplastic thyroid cancer (ATC) is highly aggressive with limited treatment options.
- Mutations in the p53 tumor suppressor gene are frequently observed in lethal ATC cases.
- The role of wild type p53 (WTp53) in mitigating ATC progression remains to be fully elucidated.
Purpose of the Study:
- To investigate the potential of WTp53 in suppressing the aggressive behavior of ATC.
- To determine the molecular mechanisms by which WTp53 counteracts the oncogenic effects of mutant p53 in ATC.
- To explore the therapeutic implications of restoring WTp53 function in ATC.
Main Methods:
- Exogenous expression of WTp53 and mutant p53 (MTp53) in human ATC cell lines (8505C).
- In vitro assays to assess cell proliferation, migration, and apoptosis.
- In vivo mouse xenograft models to evaluate tumor growth and progression.
- Single-cell RNA sequencing (scRNA-seq) to analyze differential gene expression and pathway alterations.
Main Results:
- Exogenous WTp53 expression inhibited 8505C cell proliferation and migration, and induced apoptosis by upregulating BAX and PUMA.
- WTp53 expression suppressed tumor growth in mouse xenografts, decreasing proliferation marker Ki-67 and increasing apoptosis markers (cleaved caspase-3, BAX, PUMA).
- scRNA-seq revealed distinct gene expression patterns in WTp53-expressing tumors, identifying pathway alterations that attenuate oncogenic mutant p53 activity, including suppression of the TNFα/NFκB inflammatory pathway.
Conclusions:
- Restoring WTp53 function effectively counteracts the aggressive phenotype of ATC cells, both in vitro and in vivo.
- WTp53 exerts its tumor-suppressive effects by inhibiting proliferation, promoting apoptosis, and modulating key oncogenic pathways, including inflammation.
- These findings highlight the potential of utilizing genome editing technologies like CRISPR/Cas9 to restore WTp53 function for novel ATC therapeutic strategies.
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