Abstract
Abstract Prognosis of gastric cancer (GC) remains poor and the key players in its molecular pathogenesis are unknown at present. There is therefore a critical need to identify novel prognostic factors of GC. Dedicator of cytokinesis represents a protein family belonging to atypical Rho guanine nucleotide exchange factors (GEF) for Rac and/or Cdc42 GTPases. Dedicator of cytokinesis-x, a member of the Dock-C subfamily, exchanges GDP for GTP for Rac1 and Cdc42, both in vitro and in vivo. Here, we identified Dedicator of cytokinesis-x as an independent biomarker for GC prognosis. Elevated Dedicator of cytokinesis-x expression was associated with significantly shorter cumulative survival in both univariate and multivariate analyses. Moreover, higher dedicator of cytokinesis-x expression is positively correlated with tumor size, depth of invasion, lymph node metastasis, vascular invasion and pathological stage. To establish the downstream effectors of dedicator of cytokinesis-x, we analyzed the genes in relation to dedicator of cytokinesis-x expression using three independent clinical GC cohorts. Genes displaying a positive correlation with dedicator of cytokinesis-x were subsequently subject to gene ontology analysis and shown to be significantly involved in the WNT/β-catenin signaling pathway. Depletion of dedicator of cytokinesis-x suppressed cell proliferation, chemo- and radio-resistance, metastasis, oncosphere formation ability and tumorigenicity as well as expression of gastric cancer stem cell (CSC) markers. Dedicator of cytokinesis-x depletion was accompanied by a concomitant decrease in CD44, CD133 and nuclear β-catenin expressions. Moreover, interactions between dedicator of cytokinesis-x and β-catenin were observed in the nucleus of GC cells. This finding suggested that dedicator of cytokinesis-x may act as a tumor promoter through WNT/β-catenin activation. Citation Format: Hsiang-Cheng Chi, Kwang-Huei Lin. Dedicator of cytokinesis-x promotes chemo and radioresistance of gastric cancer by modulating WNT signaling and cancer stem cell traits [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4870.
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