7092 Blocking of Aggressive Tumor Progression of Anaplastic Thyroid Cancer by p53

Abstract Disclosure: E. Hwang: None. R. Chari: None. T. Kimura: None. S. Cheng: None. Background: Anaplastic thyroid cancer (ATC) is the most aggressive form of thyroid cancer, with very limited treatment options. Patients succumb to death within 6-12 months after diagnosis. It has been observed that mutations of p53, occurring as tumorigenesis progresses, is associated with the aggressiveness of ATC. The present studies tested the hypothesis that wild type p53 (WTp53) could block tumor progression and mitigate its aggressiveness. Methods: We used human 8505C cells as a model, derived from human ATC tumors, harboring BRAFV600E mutation and one allele of mutated p53C742G. We re-expressed WTp53 or mutant p53C742G into 8505C cells (8505C-WTp53 or 8505C-MTp53 cells, respectively) via lentiviral transduction. We analyzed the effects of exogenous expressed WTp53 and mutant p53 on cell proliferation, apoptosis, and migration in vitro and the progression of tumors in vivo mouse xenograft models. Results: We showed that p53 proteins were more abundantly expressed in 8505C-WTp53 or 8505C-MTp53 cells than the parental 8505C cells. Using WTp53 luciferase reporter (PG-13), we demonstrated that the expressed WTp53 was functional as the transcription activity of p53 was higher than the parental 8505C cells. Consistently, in 8505C-MTp53, the reporter activity of PG-13 was not detected. The expressed WTp53 inhibited cell proliferation and decreased cell migration. Immunohistochemical analysis (IHC) showed decreased proliferation marker Ki67 and increased cleaved caspase-3, indicating the induction of apoptosis in 8505C-WTp53 cells. Importantly, we found that the NIS expression was increased in 8505C-WTp53 cells, but not in 8505C-MTp53 cells, as compared with 8505C cells. Xenograft studies showed that tumor progression was inhibited in nude mice injected with 8505C-WTp53 cells as compared with tumors induced by 8505C parental cells and 8505C-MTp53 cells. Consistent with in vitro findings, IHC demonstrated decreased proliferation marker Ki67 and increased cleaved caspase-3 proteins in tumors induced by 8505C-WTp53 cells. Furthermore, the expression of apoptotic regulators such as BAX and PUMA, known as p53 target genes, were elevated in 8505C-WTp53 cultured cells and in 8505C-WTp53-induced tumors, indicating induction of apoptosis. Conclusions: Our findings showed that the aggressiveness of ATC, caused by mutant p53 in late stage of tumor progression, can be mitigated by exogenous expression of WTp53. These results provided new insights into the deleterious actions of mutation of p53 in ATC tumor development. Importantly, our studies revealed that targeting p53 in ATC could be considered as a potential therapeutic opportunity. Presentation: 6/3/2024