Abstract 3546: miRNA expression of spontaneous non-small cell lung cancers in p53 mutant transgenic mice following exposure to PRIMA-1

Abstract

The tumor suppressor protein p53 is a key regulator of cell cycle control, apoptosis, and genomic stability in response to various cellular stresses. Loss of function of p53 causes an inability by the cell to regulate these important processes and results in uncontrolled cell proliferation, which leads to tumor growth. Mutations in the TP53 gene are commonly associated with cancers, and for this reason TP53/p53 is one of the most important genes in cancer research. PRIMA-1 targets mutated p53 protein and has been shown to restore its wild type function and to induce apoptosis in human tumor cells, but the underlying mechanisms behind it are still not well understood. Micro RNAs (miRNAs) are small, noncoding RNA molecules that act as gene expression regulators. The involvement of miRNA in restoring tumor suppressor function of mutant p53 by Prima-1 remains unclear. The aim of this research is to investigate the associations between expression of miRNA and the PRIMA-1 anticancer treatment. We have developed a lung tumor model in transgenic mice in which the human mutant p53(273H) is expressed in a lung specific manner, under the control of the surfactant protein C promoter. These mice developed lung adenocarcinomas at an age range of 12-15 months. A micro-CT scanner was used on the mice to screen for lung tumors. To evaluate feasibility and preliminary activity of PRIMA-1 on the murine spontaneous lung tumor, we treated 4 lung tumor bearing mice via intraperitoneal (i.p.) injection with PRIMA-1 at a dose of 100 mg/kg in 0.2 ml PBS every other day for two weeks. A control group containing 3 tumor bearing mice was treated with PBS only. After two weeks of treatment, all mice were then sacrificed for tissue collection. Total RNA was isolated with Trizol method from the frozen lung tumor tissues and matching lung tissues. miRNA array was carried out with a NanoString counter. miRNA expression level was compared between the treated and control groups. After comparing 599 miRNA expressions in lung tumor tissue between PRIMA-1 treated and non-treated mice, 26 miRNAs were changed at least 3-fold. From these 26, 23 of were decreased and only 3 were increased. Of particular interest was that 9 miRNAs changed at least 6 folds post Prima-1 treatment as comparing to control group. These were miR-194, miR-1937a, 1937b, miR-34c, miR-192, miR-1949, miR-2135, miR-3472, miR-712, and miR-1931. Because PRIMA-1 restores the tumor suppression function of mutant p53 and to induce cell cycle arrest or apoptosis in tumor cells containing mutant p53, PRIMA-1 may act as an anti-cancer drug through regulating miRNAs. Because the great majority of the miRNA expression levels among the miRNA with bigger expression changes in PRIMA-1 treated group comparing to the non-treated controls are reduced, it implies that these miRNAs may promote tumor development. Mir-194, for example, has been reported to have tumor suppressor function in lung tissue. Citation Format: Javier A. Feito, Abeer Almiman, Li Gao, Shirley Tang, Kathleen Dotts, Miguel Villalona-Calero, Wenrui Duan. miRNA expression of spontaneous non-small cell lung cancers in p53 mutant transgenic mice following exposure to PRIMA-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3546.