The <i>H19-PEG10/IGF2BP3</i> axis promotes gastric cancer progression in patients with high lymph node ratios

Abstract

// Satoru Ishii 1 , Keishi Yamashita 1 , Hiroki Harada 1 , Hideki Ushiku 2 , Toshimichi Tanaka 1 , Nobuyuki Nishizawa 1 , Keigo Yokoi 1 , Marie Washio 1 , Akira Ema 1 , Hiroaki Mieno 1 , Hiromitsu Moriya 1 , Kei Hosoda 1 , Mina Waraya 3 , Hiroshi Katoh 1 and Masahiko Watanabe 1 1 Department of Surgery, Kitasato University School of Medicine, Sagamihara, Japan 2 Department of Surgery, Kitasato University Medical Center, Saitama, Japan 3 Department of Surgery, Sagamino Hospital, Sagamihara, Japan Correspondence to: Masahiko Watanabe, email: gekaw@med.kitasato-u.ac.jp Keywords: gastric cancer, lymph node ratio, H19, PEG10, IGF2BP3 Received: February 15, 2017&nbsp;&nbsp;&nbsp;&nbsp; Accepted: June 06, 2017&nbsp;&nbsp;&nbsp;&nbsp; Published: August 05, 2017 ABSTRACT We previously demonstrated that the lymph node ratio (LNR) is a prognostic factor associated with EGFR expression, among first priority genes amplified or overexpressed in cancer. Here, we investigated the associations between high LNR and second, third, and fourth priority genes. We performed mRNA expression microarray analysis of tumor tissue from patients with stage III gastric cancer and high or low LNRs. Candidate high LNR-associated genes were further evaluated in 39 patients with stage III gastric cancer. The functional relevance of these genes was evaluated in gastric cancer cell lines. We focused on five genes: H19 , PEG10 , IGF2BP3 , CD177, and PGA3 . H19 and PEG10 were confirmed as high LNR-associated genes. H19 , PEG10 , and IGF2BP3 were found to promote each other&rsquo;s expression. Knocking down H19 or PEG10 using RNAi decreased cell proliferation, invasion, anchorage-independent growth, and chemoresistance. These genes had a mutual relationship in MKN7 cells. H19 knockdown decreased expression of epithelial-mesenchymal transition-associated genes in MKN74 cells to suppress transformation. Thus, H19 promotes epithelial-mesenchymal transition in gastric cancer and is a potential therapeutic target.