Abstract
Abstract Although runt-related transcription factor 1 (RUNX1) is well known for its context-dependent oncogenic properties in various malignancies, its role in gastric cancers has been poorly defined. Up-regulation of receptor tyrosine kinase (RTK) ErbB2/HER2 signaling pathway is encountered in the vast majority of gastric cancer cases and contributes to the initiation and maintenance of these cancer cells. This signaling cascade is partly yet arbitrary mediated by son of sevenless gene 1 (SOS1), which functions as an adaptor protein in RTK cascades. Herein we report that RUNX1 regulates ErbB2/HER2 signaling pathway in gastric cancer cells through transcriptionally regulating SOS1 expressions, rendering itself an ideal target in anticancer strategies. Mechanistically, RUNX1 interacts with the consensus RUNX1 binding sequence (5’-TGTGGT-3’) located in the proximal promoter region of SOS1 and positively regulates it. Short hairpin RNA (shRNA)-mediated knockdown of RUNX1 in the gastric cancer cell line MKN45 led to the decreased expression of SOS1 and of phosphorylated form of ErbB2/HER2 as well as the deactivation of its downstream targets such as AKT and ERK. RUNX1 knockdown subsequently induced cell cycle arrest at G0/G1 phase and successive apoptotic cell death in MKN45 cells. Silencing of HER2 or SOS1 in MKN45 cells unalterably suppressed the proliferation of these cancer cells, highlighting the importance of this ErbB2/HER2 signaling cascade in the maintenance of gastric cancer cells. We also found that SOS1 is one of the most consistently up-regulated genes in RUNX1-high expressing primary gastric cancer cells derived from previously reported human clinical samples. These data collectively indicates that inhibition of RUNX1 could be a legitimate therapeutic choice in the management of gastric cancers. Lastly, we examined the efficacy of a novel small molecule specifically binds and inhibits RUNX1 (we named it as CM). Intriguingly, CM was exceptionally effective against MKN45 cells (IC50 value at 403.5 nM). Besides, CM was well-tolerated in mice and fabulously suppressed the growth of xenotransplanted MKN45 cells in immunodeficient mice in vivo. Taken together, our work identified a novel interaction of RUNX1 and ErbB2/HER2 signaling pathway, paving a new way for the management of dismal-prognostic advanced stage HER2-positive gastric cancer patients. Citation Format: Yoshihide Mitsuda, Ken Morita, Shintaro Maeda, Kensho Suzuki, Gengo Kashiwazaki, Junichi Taniguchi, Toshikazu Bando, Hiroshi Sugiyama, Souichi Adachi, Yasuhiko Kamikubo. RUNX1 positively regulates ErbB2/HER2 signaling pathway through modulating the expression of SOS1 in gastric cancer cells [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 1530. doi:10.1158/1538-7445.AM2017-1530
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