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Background/Aims: Neurotensin (NTS), an intestinal hormone, is profoundly implicated in cancer progression through binding its primary receptor NTSR1. The conserved Wnt/ß- Catenin pathway regulates cell proliferation and differentiation via activation of the ß-catenin/T-cell factor (TCF) complex and subsequent modulation of a set of target genes. In this study, we aimed to uncover the potential connection between NTS/NTSR1 signaling and Wnt/ß- Catenin pathway. Methods: Genetic silencing, pharmacological inhibition and gain-of-function studies as well as bioinformatic analysis were performed to uncover the link between NTS/NTSR1 signaling and Wnt/ß-Catenin pathway. Two inhibitors were used in vivo to evaluate the efficiency of targeting NTS/NTSR1 signaling or Wnt/ß-Catenin pathway. Results: We found that NTS/NTSR1 induced the activation of mitogen-activated protein kinase (MAPK) and the NF-κB pathway, which further promoted the expression of Wnt proteins, including Wnt1, Wnt3a and Wnt5a. Meanwhile, the mRNA and protein expression levels of NTSR1 were increased by the Wnt pathway activator Wnt3a and decreased by the Wnt inhibitor iCRT3 in glioblastoma cells. Furthermore, pharmacological inhibition of NTS/NTSR1 or Wnt/ß-Catenin signaling suppressed tumor growth in vitro and in vivo. Conclusion: These results reveal a positive feedback loop between NTS/NTSR1 and Wnt/ß-Catenin signaling in glioblastoma cells that might be important for tumor development and provide potential therapeutic targets for glioblastoma. [ABSTRACT FROM AUTHOR]

Tumor growth is fueled by subset of cells with stem cell properties (Cancer stem cells, CSCs). While persistent activation of Wnt/β-catenin signaling confers CSC properties, it remains unclear how epigenetic modifications regulate Wnt target genes to dictate their self-renewal. Here, we report a novel Wnt-responsive epigenetic switch for CSC maintenance through activating the stem cell transcription factor ASCL2 in gastric carcinoma (GC). We characterize ASCL2-expressing (ASCL2+) GC cells as a subset of Wnt-responsive CSCs that depend on ASCL2 for self-renewal. High-throughput RNAi screening uncovers that the histone methyltransferase SMYD3 determines H3K4me3 status at the ASCL2 locus to promote ASCL2 expression. Moreover, SMYD3 may be transcriptionally activated by the β-catenin/TCF4 complex, indicating that the SMYD3-ASCL2 axis may be an integral component of Wnt signaling. Consistently, SMYD3 maintains self-renewal and tumorigenicity of ASCL2+ CSCs largely through inducing ASCL2. Clinically, overexpression of SMYD3 and ASCL2 are associated with malignant progression and poor patient outcomes in GC. Together, these findings define a Wnt-responsive CSC pathway that could be exploited to identify essential regulators of the signaling output, and reveal SMYD3 as an epigenetic target for eliminating CSCs in human cancers. [ABSTRACT FROM AUTHOR]