Abstract 1843: Identification of peritoneal dissemination-related genes in gastric cancer

Abstract

Abstract INTRODUCTION: Peritoneal dissemination (PD) is highly frequent and incurable metastasis in gastric cancer (GC). The mechanism causing PD is still poorly understood. In this study, we aimed to identify the genes responsible for PD using several large-scale public microarray databases. MATERIALS AND METHODS: First, we identified the candidate genes, which satisfied the all-4 outlines using microarray data as follow: 1) overexpressed in GC cell lines with high potential of PD; 2) overexpressed in GC patients with PD in Singapore from Duke-NUS Graduate Medical School; 3) overexpressed in tumor tissues in GC from TCGA database; 4) poor prognostic factor in GC from TCGA database. Next, we measured the expression of candidate genes by Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and performed clinicopathological studies of the expression in 146 Japanese GC patients who underwent surgery in our hospital. Finally, we performed gene set enrichment analysis (GSEA) with TCGA database to elucidate the correlation between candidate genes and gene sets that are associated with tumorigenesis or tumor progression in GC. Then, we examined the correlation between the candidate genes and one of the gene sets that were identified through GSEA by qRT-PCR in 5 GC cell lines (MKN7, KATO3, AGS, HSC39, 39As). RESULTS: 1. We identified Arl4c (ADP-ribosylation factor-like 4c) as a PD candidate gene by above our screening system. 2. The expression of Arl4c was significantly higher in tumor tissues than in corresponding normal tissues in Japanese GC patients (p<0.0002). In clinicopathological analysis, the high expression group of Arl4c was significantly associated with depth of invasion (p<0.01) and PD (p<0.05). Multivariate analysis indicated that high expression of Arl4c was an independent prognostic factor (hazard ratio 2.20; 95% CI 1.06-4.97; p< 0.03) among all clinicalpathological factors in GC. 3. GSEA revealed that the expression of Arl4c positively correlated with epithelial-mesenchymal transformation (EMT) gene set. In the 5 GC cell lines, the expression of Arl4c negatively correlated with the expression of cdh1, which was well known as a down-regulated gene in EMT. CONCLUSION: Arl4c is a member of the ADP-ribosylation factor family of GTP-binding proteins and plays a role in cholesterol transport. Recent study revealed that Arl4c regulates YAP/TAZ pathway that is well known to induce EMT and promotes tumorigenesis in lung or colorectal cancer. Our results suggest that Arl4c should be involved in PD via EMT induced by the YAP/TAZ pathway, resulting in a poor prognostic marker in GC. Arl4c may be a novel biomarker and a therapeutic target for PD in GC. Citation Format: Qingjiang Hu, Shiya Kidogami, Sho Nambara, Hisateru Komatsu, Kuniaki Sato, Yushi Ogawa, Tomoko Saito, Shotaro Sakimura, Hidenari Hirata, Ryutaro Uchi, Naoki Hayashi, Tomohiro Iguchi, Takaaki Masda, Shuhei Ito, Hidetoshi Eguchi, Yoshihiko Maehara, Koshi Mimori. Identification of peritoneal dissemination-related genes in gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1843.