The H19-PEG10/IGF2BP3 axis promotes gastric cancer progression in patients with high lymph node ratios
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Satoru Ishii1, Keishi Yamashita1, Hiroki Harada1, Hideki Ushiku2, Toshimichi Tanaka1, Nobuyuki Nishizawa1, Keigo Yokoi1, Marie Washio1, Akira Ema1, Hiroaki Mieno1, Hiromitsu Moriya1, Kei Hosoda1, Mina Waraya3, Hiroshi Katoh1 and Masahiko Watanabe1
1Department of Surgery, Kitasato University School of Medicine, Sagamihara, Japan
2Department of Surgery, Kitasato University Medical Center, Saitama, Japan
3Department of Surgery, Sagamino Hospital, Sagamihara, Japan
Masahiko Watanabe, email: [email protected]
Keywords: gastric cancer, lymph node ratio, H19, PEG10, IGF2BP3
Received: February 15, 2017 Accepted: June 06, 2017 Published: August 05, 2017
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’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.
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