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

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-HT1D receptor (5-HT1DR) was associated with Wnt signaling pathway and advanced tumor stage. The underlying mechanism of 5-HT1DR-promoted tumor invasion was through its activation on the Axin1/beta-catenin/MMP-7 pathway. In an orthotopic colorectal cancer mouse model, we demonstrated that a 5-HT1DR antagonist (GR127935) effectively inhibited tumor metastasis through targeting Axin1. Furthermore, in intestinal epithelium cells, we observed that 5-HT1DR played an important role in cell invasion via Axin1/beta-catenin/MMP-7 pathway. Together, our findings reveal an essential role of the physiologic level of 5-HT1DR in pulmonary metastasis of colorectal cancer.