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Abstract 2539: Mutant TP53 action in lung dictated by the cell microenvironment

TP53 is a well-known tumor suppressor protein involved in many anti-tumor processes such as apoptosis, DNA repair, and cell cycle arrest. Codon 273 is one of the most frequently mutated sites among all p53 mutant types in human lung cancer. Recently, it has been discovered that TP53 and its mutants influence the expression of cancer-relevant microRNAs and vice-versa. Although many experiments have been performed on cell lines, far fewer experiments were geared toward how TP53 mutations affect miRNA expression in complex, in vivo settings. In addition to this, there are competing viewpoints on how TP53-273H could interact with wild type TP53. To investigate the mechanism involved in the oncogenic potential of mutant TP53 protein in vivo, TP53+/+/TG273H transgenic mice were bred into p53 null background. At the age of 5-6 weeks, TP53−/−; TP53−/-/TG273H; TP53+/+; and TP53+/+/TG273H mice were used to evaluate the expression of micro RNAs (miRNAs) as well as TP53 downstream genes. Based on the nanoString miRNA analysis, TP53−/- 273H mice exhibits decreased expression of miR-205, 206, and 1274a when compared against TP53−/− mice. However, TP53+/+ 273H mice resulted in increased expression of these miRNAs when compared against wild-type mice without mutant TP53 (TP53+/+). When comparing p53−/− knockout mice with wild-type mice, miRNAs 205, 206, and 1274a all increased at least 3-fold compared to wild-type. TP53−/− 273H mice exhibited widespread decrease of miRNA expression levels when compared against TP53+/+ 273H mice. The results suggest that the biological function of the TP53-273H is dictated by the cell microenvironment, especially the presence/absence of the wild type TP53 through dominant-negative effects in lung tissues. Mutant TP53-273H exerts oncogenic/tumor suppressor effects through specific miRNAs and their target gene networks. Citation Format: Christopher Yin, Li Gao, Miguel A. Villalona-Calero, Wenrui Duan. Mutant TP53 action in lung dictated by the cell microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2539.