5-hydroxytryptamine receptor (5-HT1DR) promotes colorectal cancer metastasis by regulating Axin1/β-catenin/MMP-7 signaling pathway

• Published in: Oncotarget 2015-09, Vol.6 (28), p.25975-25987
• Main Authors: Sui, Hua, Xu, Hanchen, Ji, Qing, Liu, Xuan, Zhou, Lihong, Song, Haiyan, Zhou, Xiqiu, Xu, Yangxian, Chen, Zhesheng, Cai, Jianfeng, Ji, Guang, Li, Qi
• Format: Article
• Language: English
• Subjects: Animals; Axin Protein - genetics; Axin Protein - metabolism; beta Catenin - genetics; beta Catenin - metabolism; Blotting, Western; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - genetics; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; HT29 Cells; Humans; Immunohistochemistry; Male; Matrix Metalloproteinase 7 - genetics; Matrix Metalloproteinase 7 - metabolism; Mice, Nude; Middle Aged; Neoplasm Metastasis; Oxadiazoles - pharmacology; Piperazines - pharmacology; Receptor, Serotonin, 5-HT1D - genetics; Receptor, Serotonin, 5-HT1D - metabolism; Research Paper; Reverse Transcriptase Polymerase Chain Reaction; Serotonin Antagonists - pharmacology; Signal Transduction - drug effects; Signal Transduction - genetics; Tumor Burden - drug effects; Tumor Burden - genetics; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.4543

Overexpression of 5-hydroxytryptamine (5-HT) in human cancer contributes to tumor metastasis, but the role of 5-HT receptor family in cancer has not been thoroughly explored. Here, we report overexpression of 5-HT(1D) receptor (5-HT(1D)R) was associated with Wnt signaling pathway and advanced tumor stage. The underlying mechanism of 5-HT(1D)R-promoted tumor invasion was through its activation on the Axin1/β-catenin/MMP-7 pathway. In an orthotopic colorectal cancer mouse model, we demonstrated that a 5-HT(1D)R antagonist (GR127935) effectively inhibited tumor metastasis through targeting Axin1. Furthermore, in intestinal epithelium cells, we observed that 5-HT(1D)R played an important role in cell invasion via Axin1/β-catenin/MMP-7 pathway. Together, our findings reveal an essential role of the physiologic level of 5-HT(1D)R in pulmonary metastasis of colorectal cancer.