Abstract 4786: Potential role of p53-Mieap-regulated mitochondrial quality control as a tumor suppressor in gastric and esophageal cancers Potential role of p53/Mieap-regulated mitochondrial quality control as a tumor suppressor in gastric, esophageal and breast cancers

Abstract

Abstract [Background] Despite its early diagnosis and improved intensive treatments, gastric cancer (GC) remains the third leading cause of death throughout the world. In particular among upper gastrointestinal cancers, it is most prevalent in eastern Asia including Japan, Korea, and China. p53 is a transcription factor that activates the expression of various downstream genes in response to DNA damage. The central functions of this protein in tumor suppression are cell cycle arrest, apoptosis, DNA repair, and anti-angiogenesis. Mitochondria-eating protein (Mieap) is a p53-target that plays an important role in mitochondrial quality control (MQC). Mieap has been reported to have a critical role in tumor suppression in colorectal and breast cancers. Here, we investigated its role as a tumor suppressor in gastric cancer (GC) and esophageal cancer (EC). [Materials and Methods] To investigate the role of Mieap, Mieap-expressing adenovirus (Ad-Mieap) was used to infect GC cells, which were then analyzed by FACS, western blot, and caspase assays. Next, we evaluated the potential disruption of the p53-Mieap-regulated MQC pathway in vivo. Methylation-specific PCR (MPS) for Mieap, NIX, and BNIP3 promoters and p53 mutation detection were performed using genomic DNA from cryopreserved surgical specimens. [Results] Exogenous Mieap in GC cells induced the formation of vacuole-like structures (called MIVs, Mieap-induced vacuoles) and caspase-dependent apoptosis, with the activation of both caspase-3 and caspase-9. In particular, NIX, a mitochondrial apoptotic factor was involved in this phenotype. Of 47 GC patient samples, promoter methylation of Mieap, BNIP3, and NIX was identified in two (4.3%), 29 (61.7%), and zero (0%) specimens, respectively. In total, 33 GC patient samples (70.2%) revealed inactivation of the p53/Mieap-regulated MQC pathway. Interestingly, we found that the BNIP3 promoter in the normal epithelium was highly methylated in 18 of 47 GC cases (38.3%). In EC patients, this MQC pathway was inactivated in ten of 12 patients (83.3%). [Conclusion] These results indicate that p53/Mieap-regulated MQC has a critical role in not only breast cancer but also gastrointestinal cancer suppression, possibly in part through the mitochondrial apoptotic pathway. Citation Format: Manabu Futamura, Hitoya Sano, Siqin Gaowa, Akira Nakakami, Kazuhiro Yoshida, Hirofumi Arakawa. Potential role of p53-Mieap-regulated mitochondrial quality control as a tumor suppressor in gastric and esophageal cancers Potential role of p53/Mieap-regulated mitochondrial quality control as a tumor suppressor in gastric, esophageal and breast cancers [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 4786.