Abstract 1336: Significance of SERPINE2 expression in peritoneal metastasis in gastric carcinoma
Authors: Kuroda Daisuke , Kurashige Junji , Sawayama Hiroshi , Iwatsuki Masaaki , Uchihara Tomoyuki , Toihata Tasuku , Oda Eri , Yagi Taisuke , Eto Tsugio , Miyake Keisuke , Ouchi Mayuko , Nakamura Kenichi , Kinoshita Koichi , Mima Kousuke , Ishimoto Takatsugu , Sakamoto Yasuo , Baba Yoshifumi , Yoshida Naoya , Mimori Koshi , Baba Hideo 
Published: July 2017

Background: Peritoneal metastasis is one of the most frequent causes of death in patients with advanced gastric carcinoma (GC). However, molecular mechanisms driving peritoneal dissemination still remain poorly understood. Here, we aimed to give new insights to the molecular mechanisms that drive the peritoneal dissemination of GC. This study identified candidates of potential regulators of peritoneal dissemination and focused on the significance of one of them in vitro experiments and clinical samples.

Methods: We utilized previously reported combined expression analysis with two cell lines and samples and 200 GC patients to identify driver genes of peritoneal dissemination. The cell lines consist of HSC58, an established cell lines from scirrhous type primary GC and its progeny cell line, 58As9, with in vivo-selected highly peritoneal metastatic potential. In vitro experiments, we utilized the two gastric cancer cell lines, 58As9 and NUGC4 and evaluated the effect of SERPINE2 knockdown on proliferation, spheroid formation, invasion, and motility. As for evaluation of clinical samples, 176 primary gastric carcinomas were included, which were obtained from patients who underwent curative gastrectomy in Kumamoto university between 2005 and 2015. We evaluated expression of SERPINE2 in immunohistochemistry and divided the cohort into two groups by SERPINE2 expression and analyzed relationship with clinicopathological factors and survival.

Results: Enrichment analyses of the profile of the peritoneal dissemination-associated expression signature revealed that poor prognosis and peritoneal metastasis was related with the two pathways, focal adhesion (FDR q=0.00195) and extracellular matrix (FDR q=0.00195). Among the genes related with extracellular matrix, Serine Proteinase Inhibitor, Clade E, Member 2 (SERPINE2) was found to be highly expressed in 58As9 compared with HSC58, and we focused on SERPINE2 as a candidate of potential regulators of peritoneal dissemination. In vitro experiments, the SERPINE2 knockdown was related with decrease in cell motility and invasion, but not with decrease in proliferation, spheroid formation. Immunohistochemistry analysis of the clinical samples revealed higher SERPINE2 expression was significantly related with invasion of serosa and lymphatic vessels, and lymph node matastasis, and peritoneal metastatic metastasis. Survival analysis also revealed SERPINE2 expression was related with poor peritoneal recurrence-free survival (p=0.038), and peritoneal metastasis-specific survival (p=0.036).

Conclusion: We found SERPINE2 as a candidate of driving molecules of peritoneal metastasis partly because it promotes invasive potential. Further study including in vivo study is required to reveal relationship of SERPINE2 with the other molecules and pathways.

Citation Format: Daisuke Kuroda, Junji Kurashige, Hiroshi Sawayama, Masaaki Iwatsuki, Tomoyuki Uchihara, Tasuku Toihata, Eri Oda, Taisuke Yagi, Tsugio Eto, Keisuke Miyake, Mayuko Ouchi, Kenichi Nakamura, Koichi Kinoshita, Kousuke Mima, Takatsugu Ishimoto, Yasuo Sakamoto, Yoshifumi Baba, Naoya Yoshida, Koshi Mimori, Hideo Baba. Significance of SERPINE2 expression in peritoneal metastasis in gastric carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1336. doi:10.1158/1538-7445.AM2017-1336